U.S. patent application number 17/284434 was filed with the patent office on 2021-11-11 for processes for preparing functionalized cyclooctenes.
The applicant listed for this patent is The Research Foundation of the State University of New York, Tambo, Inc.. Invention is credited to Da-Ming Gou, Jose M. Mejia Oneto, Maksim Royzen, Jochem Theodoor Van Herpt, Nathan Yee, Chun-Min Zeng.
Application Number | 20210346502 17/284434 |
Document ID | / |
Family ID | 1000005769011 |
Filed Date | 2021-11-11 |
United States Patent
Application |
20210346502 |
Kind Code |
A1 |
Mejia Oneto; Jose M. ; et
al. |
November 11, 2021 |
PROCESSES FOR PREPARING FUNCTIONALIZED CYCLOOCTENES
Abstract
The present disclosure relates to processes for preparing
functionalized cyclooctenes and the synthetic intermediates
prepared thereby.
Inventors: |
Mejia Oneto; Jose M.; (San
Francisco, CA) ; Yee; Nathan; (San Francisco, CA)
; Van Herpt; Jochem Theodoor; (Groningen, NL) ;
Zeng; Chun-Min; (Cranbury, NJ) ; Gou; Da-Ming;
(Cranbury, NJ) ; Royzen; Maksim; (Albany,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tambo, Inc.
The Research Foundation of the State University of New
York |
San Francisco
Albany |
CA
NY |
US
US |
|
|
Family ID: |
1000005769011 |
Appl. No.: |
17/284434 |
Filed: |
October 10, 2019 |
PCT Filed: |
October 10, 2019 |
PCT NO: |
PCT/US19/55707 |
371 Date: |
April 9, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62744041 |
Oct 10, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
C07C 2601/18 20170501; A61K 38/14 20130101; C07D 493/08 20130101;
C07D 207/46 20130101; C07C 51/47 20130101; A61K 31/704 20130101;
C07C 62/30 20130101; A61K 38/07 20130101; C07C 62/32 20130101; A61K
38/15 20130101; C07C 67/327 20130101 |
International
Class: |
A61K 47/14 20060101
A61K047/14; A61K 31/704 20060101 A61K031/704; A61K 38/07 20060101
A61K038/07; A61K 38/14 20060101 A61K038/14; A61K 38/15 20060101
A61K038/15; C07C 51/47 20060101 C07C051/47; C07C 67/327 20060101
C07C067/327; C07C 62/32 20060101 C07C062/32; C07C 62/30 20060101
C07C062/30; C07D 207/46 20060101 C07D207/46; C07D 493/08 20060101
C07D493/08 |
Claims
1. A process of preparing a compound of formula I, or a salt
thereof: ##STR00118## wherein R.sup.1 is selected from the group
consisting of --OR.sup.4, optionally substituted heterocyclyl, and
an amino acid moiety; n is 0, 1, 2, 3 or 4; each R.sup.2 is
independently C.sub.1-4alkyl, C.sub.1-4haloalkyl, and
C.sub.1-4alkoxy; and D is a payload moiety; R.sup.4 is hydrogen or
C.sub.1-4 alkyl; comprising contacting a compound of formula II:
##STR00119## with HO--R.sup.4, an optionally substituted
heterocyclyl or an amino acid moiety, or a salt thereof, and a
compound of formula III: ##STR00120## wherein each R.sup.3 is
independently C.sub.1-4 alkyl, in an organic solvent in the
presence of a base.
2. The process of claim 1, wherein the payload moiety is an
anthracycline moiety, an auristatin moiety, a glycopeptide
antibiotic moiety, or a lipopeptide antibiotic moiety.
3. The process of claim 2, wherein the payload moiety is a
doxorubicin moiety, daunorubicin moiety, monomethyl auristatin E
moiety, vancomycin moiety or daptomycin moiety.
4. The process of any of claims 1-3, wherein R.sup.1 is an amino
acid moiety, an alanine moiety or a glycine moiety.
5. The process of any of claims 1-4, wherein the compound of
formula III is N,O-bis(trimethylsilyl)acetamide.
6. The process of any of claims 1-5, wherein the compound of
formula I is represented by formula IA: ##STR00121## wherein
R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
R.sup.4 is hydrogen or C.sub.1-4 alkyl; R.sup.5 is hydrogen or
C.sub.1-4 alkyl; and D is a payload moiety; and the compound of
formula II is represented by formula IIA: ##STR00122##
7. The process of any of claims 1-5, further comprising preparing
the compound of formula II by reacting a compound of formula IV:
##STR00123## with a payload moiety, or a salt thereof, in an
organic solvent in the presence of a base.
8. The process of claim 6, wherein the compound of formula IV is
represented by formula IVA: ##STR00124##
9. A process of preparing a compound of formula X, or a salt
thereof: ##STR00125## wherein R.sup.1 is selected from the group
consisting of --OR.sup.4, an optionally substituted heterocyclyl,
and an amino acid moiety; n is 0, 1, 2, 3 or 4; each R.sup.2 is
independently C.sub.1-4alkyl, C.sub.1-4haloalkyl, and
C.sub.1-4alkoxy; and R.sup.4 is hydrogen or C.sub.1-4alkyl;
comprising contacting a compound of formula IV: ##STR00126## with
HO--R.sup.4, an optionally substituted heterocyclyl or an amino
acid, or a salt thereof, and a compound of formula III:
##STR00127## wherein each R.sup.3 is independently C.sub.1-4 alkyl,
in an organic solvent in the presence of a base.
10. The process of claim 9, wherein the compound of formula X is
represented by formula XA: ##STR00128## and the compound of formula
IV is represented by formula IVA: ##STR00129## wherein R.sup.5 is
hydrogen or C.sub.1-4 alkyl.
11. The process of claim 9, further comprising preparing the
compound of formula IV, or a salt thereof, comprising contacting a
compound of formula V, or a salt thereof: ##STR00130## with
N,N'-disuccinimidylcarbonate in an organic solvent in the presence
of a base.
12. The process of claim 11, wherein the compound of formula V is
represented by formula VA: ##STR00131## wherein R.sup.5 is hydrogen
or C.sub.1-4 alkyl.
13. A process of preparing a compound of formula I, or a salt
thereof: ##STR00132## wherein R.sup.1 is selected from the group
consisting of --OR.sup.4, optionally substituted heterocyclyl, and
an amino acid moiety; n is 0, 1, 2, 3 or 4; each R.sup.2 is
independently C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
alkoxy; D is a payload moiety; and R.sup.4 is hydrogen or C.sub.1-4
alkyl; comprising contacting a compound of formula X, or a salt
thereof: ##STR00133## with a payload moiety, or a salt thereof, in
an organic solvent in the presence of a base.
14. The process of claim 13, wherein the compound of formula I is
represented by formula IA: ##STR00134## and the compound of formula
X is represented by formula XA: ##STR00135## wherein R.sup.5 is
hydrogen or C.sub.1-4 alkyl.
15. A process of preparing a composition comprising a compound of
formula IV, or a salt thereof: ##STR00136## wherein n is 0, 1, 2,
3, or 4; and each R.sup.2 independently hydrogen or C.sub.1-4
alkyl; comprising contacting one equivalent of a compound of
formula V, or a salt thereof: ##STR00137## with 3-5 equivalents of
N,N'-disuccinimidylcarbonate in 15-25 volumes of an anhydrous
organic solvent in the presence of a base at a temperature from
15-30.degree. C. for 5-10 hours.
16. The process of claim 15, further comprising adding the
composition comprising a compound of formula IV to 40-60 volumes of
water at room temperature to form an aqueous product mixture.
17. The process of claim 16, further comprising isolating a solid
formed in the aqueous product mixture.
18. The process of claim 17, further comprising triturating the
solid in acetonitrile at a temperature of from about 30 to about
50.degree. C. to form a triturated solid.
19. The process of claim 18, further comprising isolating the
triturated solid.
20. The process of claim 15 wherein the anhydrous organic solvent
is anhydrous acetonitrile.
21. The process of any of claims 15-20, wherein the base is a
trialkylamine base.
22. The process of claim 21, wherein the base is
diisopropylethylamine.
23. The process of any of claims 15-22, wherein the compound of
formula IV is represented by formula IVA: ##STR00138## and the
compound of formula V is represented by formula VA: ##STR00139##
wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl; and R.sup.5 is
hydrogen or C.sub.1-4 alkyl.
24. A process for resolving a composition comprising one or more
stereoisomers of a compound of formula VI, or a salt thereof:
##STR00140## wherein n is 0, 1, 2, 3, or 4; each R.sup.2 is
independently C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
alkoxy; comprising the steps of: (a) contacting a composition
comprising one or more stereoisomers of formula VI with a chiral
base to provide a chiral salt of the compound of formula VI; (b)
cooling the composition of step (a); (c) isolating the chiral salt
of the compound of formula VI; and (d) hydrolyzing the chiral salt
of the compound of formula VI to provide the enantiomerically
enriched composition comprising a compound of formula VI, or a salt
thereof.
25. The process of claim 24, wherein the chiral base is
cinchonidine.
26. The process of claim 24, wherein the contacting of step (a) is
performed in a solvent selected from acetone/water or
acetone/isopropyl alcohol.
27. The process of claim 24, wherein the cooling of step (b) is
performed at a temperature at or below about 15.degree. C.
28. The process of claim 24, wherein the cooling of step (b) is at
a temperature of from about 10 to about 15.degree. C.
29. The process of claim 24, wherein the cooling of step (b) is
maintained for at least about 8 hours.
30. The process of claim 24, wherein the isolating of step (c) is
via filtration.
31. The process of claim 24, further comprising dissolving the
chiral salt of the compound of formula VI obtained from step (c) in
a suitable solvent, and repeating steps (b) and (c) prior to step
(d).
32. The process of claim 30, wherein the steps of dissolving the
chiral salt of the compound of formula VI obtained from step (c) in
a suitable solvent, and repeating steps (b) and (c) two, three,
four, five or six times prior to step (d).
33. The process of any of claims 24-32, wherein the compound of
formula VI is represented by formula VIA: ##STR00141## wherein
R.sup.5 is hydrogen or C.sub.1-4 alkyl.
34. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula VII, or a salt
thereof: ##STR00142## wherein n is 0, 1, 2, 3 or 4; each R.sup.2 is
independently C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
alkoxy; and R.sup.4 is independently hydrogen or C.sub.1-4 alkyl;
comprising sequentially contacting an enantiomerically enriched
composition of a compound of formula VI, or a salt thereof:
##STR00143## with: (i) a solution comprising KI and I.sub.2, (ii) a
base, and (iii) a hydrolyzing composition comprising a base and a
compound of formula R.sup.4--OH, to provide the enantiomerically
enriched composition of a compound of formula VII, or a salt
thereof.
35. The process of claim 34, wherein the compound of formula VII is
represented by formula VIIA: ##STR00144## and the compound of
formula VI is represented by formula VIA: ##STR00145## wherein
R.sup.5 is hydrogen or C.sub.1-4 alkyl.
36. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula VIIB, or a salt
thereof: ##STR00146## wherein R.sup.5 is hydrogen or C.sub.1-4
alkyl, comprising hydrolyzing an enantiomerically enriched
composition of a compound of formula IXB, or a salt thereof:
##STR00147## with a hydrolyzing composition comprising a base and a
compound of formula R.sup.4--OH, to provide the enantiomerically
enriched composition of a compound of formula VIIB, or a salt
thereof.
37. A process for resolving a composition comprising one or more
stereoisomers of a compound of formula VIIA, or a salt thereof:
##STR00148## wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl,
comprising the steps of: (a) contacting a composition comprising
one or more stereoisomers of formula VIIA with a chiral base to
provide a chiral salt of the compound of formula VIIA; (b) cooling
the composition of step (a); (c) isolating the chiral salt of the
compound of formula VIIA; and (d) hydrolyzing the chiral salt of
the compound of formula VIIA to provide the enantiomerically
enriched composition comprising a compound of formula VIIA, or a
salt thereof.
38. The process of claim 37, wherein the chiral base is
(R)-1-amino-2-propanol, L-phenylalaninol, (S)-phenylglycinol,
(S)-diphenyl-2-pyrrolidine methanol.
39. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula IXB, or a salt
thereof: ##STR00149## wherein R.sup.5 is hydrogen or C.sub.1-4
alkyl, comprising contacting an enantiomerically enriched
composition of a compound of formula VIIIB, or a salt thereof:
##STR00150## with a base to provide the enantiomerically enriched
composition of a compound of formula IXB, or a salt thereof.
40. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula VIIIB, or a salt
thereof: ##STR00151## wherein R.sup.5 is hydrogen or
C.sub.1-4alkyl, comprising contacting an enantiomerically enriched
composition of a compound of formula VIB, or a salt thereof:
##STR00152## with a solution comprising KI and I.sub.2 to provide
the enantiomerically enriched composition of a compound of formula
VIIIB, or a salt thereof.
41. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula VIIB, or a salt
thereof: ##STR00153## wherein R.sup.4 is hydrogen or C.sub.1-4
alkyl; and R.sup.5 is hydrogen or C.sub.1-4 alkyl; comprising the
steps of: (a) contacting an enantiomerically enriched composition
of a compound of formula VIB, or a salt thereof: ##STR00154## with
a solution comprising KI and I.sub.2 to provide an enantiomerically
enriched composition of a compound of formula VIIIB, or a salt
thereof: ##STR00155## (b) contacting the enantiomerically enriched
composition of a compound of formula VIIIB with a base to provide
an enantiomerically enriched composition of a compound of formula
IXB, or a salt thereof: ##STR00156## (c) hydrolyzing the
enantiomerically enriched composition of a compound of formula IXB,
or a salt thereof, with a hydrolyzing composition comprising a base
and a compound of formula R.sup.4--OH, to provide the
enantiomerically enriched composition of a compound of formula
VIIB, or a salt thereof.
42. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula VB, or a salt thereof:
##STR00157## wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl; and
R.sup.5 is hydrogen or C.sub.1-4 alkyl; comprising isomerizing an
enantiomerically enriched composition of a compound of formula
VIIB, or a salt thereof: ##STR00158##
43. The process of claim 42, wherein the isomerizing comprises
exposing the compound of formula VA to UV light.
44. The process of claim 42 or 43, wherein when R.sup.4 is
C.sub.1-4 alkyl, the process further comprises a hydrolyzing step
to convert R.sup.4 to hydrogen.
45. A process for the preparation of an enantiomerically enriched
composition comprising a compound of formula IVB, or a salt
thereof: ##STR00159## wherein R.sup.5 is hydrogen or
C.sub.1-4alkyl, comprising contacting an enantiomerically enriched
composition of a compound of formula VB, or a salt thereof:
##STR00160## with N,N'-disuccinimidyl carbonate (DSC) under
conditions to provide the enantiomerically enriched composition
comprising a compound of formula IVB.
46. The process of any preceding claim, wherein R.sup.2 or R.sup.5
is methyl.
47. An enantiomerically enriched composition comprising a compound
selected from Table 1, or a salt thereof: TABLE-US-00006 TABLE 1
IVC ##STR00161## IVD ##STR00162## IVE ##STR00163## VC-1
##STR00164## VD-1 ##STR00165## VE-1 ##STR00166## VIC ##STR00167##
VID ##STR00168## VIE ##STR00169## VIIC ##STR00170## VIID
##STR00171## VIIE ##STR00172## VIIIC ##STR00173## VIIID
##STR00174## VIIIE ##STR00175## IXC ##STR00176## IXD ##STR00177##
IXE ##STR00178## XC ##STR00179## XD ##STR00180## XE
##STR00181##
48. The process of any preceding claim, wherein the
enantiomerically enriched composition has a % ee of greater than
about 25%, or about 50%, or about 70%, or about 80%, or about 90%,
or about 95%, or about 98%, or about 99% or about 100%.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application No. 62/744,041, filed Oct.
10, 2018, the entirety of which is hereby incorporated by
reference.
FIELD
[0002] The present disclosure relates to processes for preparing
functionalized cyclooctenes and the synthetic intermediates
prepared thereby.
BACKGROUND
[0003] Bioorthogonal conjugation or click reactions are selective
and orthogonal (non-interacting with) functionalities found in
biological systems, and have found use in various applications in
the fields of chemistry, chemical biology, molecular diagnostics,
and medicine, where they can be used to facilitate the selective
manipulation of molecules, cells, particles and surfaces, and the
tagging and tracking of biomolecules in vitro and in vivo. These
reactions include the Staudinger ligation, the azide-cyclooctyne
cycloaddition, and the inverse-electron-demand Diels-Alder
reaction. The present disclosure provides methods for preparing
functionalized payload compositions for use in such reactions,
which have improved aqueous solubility, for delivering therapeutic
agents to a subject.
SUMMARY
[0004] The functionalized payloads according to the present
disclosure have improved aqueous solubility compared with payloads
linked to an unsubstituted cyclooctene, and therefore are more
easily formulated and administered.
[0005] Provided herein is a process of preparing a compound of
formula I, or a salt thereof:
##STR00001##
[0006] wherein
[0007] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0008] n is 0, 1, 2, 3 or 4;
[0009] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy;
[0010] D is a payload moiety; and
[0011] R.sup.4 is hydrogen or C.sub.1-4alkyl;
[0012] comprising contacting a compound of formula II:
##STR00002##
[0013] with HO--R.sup.4, an optionally substituted heterocyclyl or
an amino acid moiety, or a salt thereof, and a compound of formula
III:
##STR00003##
[0014] wherein each R.sup.3 is independently C.sub.1-4 alkyl, in an
organic solvent in the presence of a base.
[0015] Also provided is a process of preparing a compound of
formula X, or a salt thereof:
##STR00004##
[0016] wherein
[0017] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0018] n is 0, 1, 2, 3 or 4;
[0019] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy; and
[0020] R.sup.4 is hydrogen or C.sub.1-4 alkyl;
[0021] comprising contacting a compound of formula IV:
##STR00005##
[0022] with HO--R.sup.4, an optionally substituted heterocyclyl or
an amino acid moiety, or a salt thereof, and a compound of formula
III:
##STR00006##
[0023] wherein each R.sup.3 is independently C.sub.1-4alkyl, in an
organic solvent in the presence of a base.
[0024] Also provided is a process of preparing a compound of
formula I, or a salt thereof:
##STR00007##
[0025] wherein
[0026] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0027] n is 0, 1, 2, 3 or 4;
[0028] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy;
[0029] D is a payload moiety; and
[0030] R.sup.4 is hydrogen or C.sub.1-4 alkyl;
[0031] comprising contacting a compound of formula X, or a salt
thereof:
##STR00008##
[0032] with a payload moiety, or a salt thereof, in an organic
solvent in the presence of a base.
[0033] Also provided is a process of preparing a composition
comprising a compound of formula IV, or a salt thereof:
##STR00009##
[0034] wherein
[0035] n is 0, 1, 2, 3, or 4; and
[0036] each R.sup.2 independently hydrogen or C.sub.1-4 alkyl;
[0037] comprising contacting one equivalent of a compound of
formula V, or a salt thereof:
##STR00010##
[0038] with 3-5 equivalents of N,N'-disuccinimidylcarbonate in
15-25 volumes of an anhydrous organic solvent in the presence of a
base at a temperature from 15-30.degree. C. for 5-10 hours.
[0039] Also provided is a process for resolving a composition
comprising one or more stereoisomers of a compound of formula VI,
or a salt thereof:
##STR00011##
[0040] wherein
[0041] n is 0, 1, 2, 3, or 4;
[0042] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy;
[0043] comprising the steps of:
[0044] (a) contacting a composition comprising one or more
stereoisomers of formula VI with a chiral base to provide a chiral
salt of the compound of formula VI;
[0045] (b) cooling the composition of step (a);
[0046] (c) isolating the chiral salt of the compound of formula VI;
and
[0047] (d) hydrolyzing the chiral salt of the compound of formula
VI to provide the enantiomerically enriched composition comprising
a compound of formula VI, or a salt thereof.
[0048] In certain embodiments, the process comprises repeating
steps (b) and (c) prior to step (d).
[0049] Also provided is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VII, or a salt thereof:
##STR00012##
[0050] wherein
[0051] n is 0, 1, 2, 3 or 4;
[0052] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy; and
[0053] R.sup.4 is independently hydrogen or C.sub.1-4 alkyl;
[0054] comprising sequentially contacting an enantiomerically
enriched composition of a compound of formula VI, or a salt
thereof:
##STR00013##
[0055] with: (i) a solution comprising KI and I.sub.2, (ii) a base,
and (iii) a hydrolyzing composition comprising a base and a
compound of formula R.sup.4--OH, to provide the enantiomerically
enriched composition of a compound of formula VII, or a salt
thereof.
[0056] Also provided is a process for resolving a composition
comprising one or more stereoisomers of a compound of formula VIIA,
or a salt thereof:
##STR00014##
[0057] wherein
[0058] R.sup.5 is hydrogen or C.sub.1-4 alkyl, comprising the steps
of:
[0059] (a) contacting a composition comprising one or more
stereoisomers of formula VIIA with a chiral base to provide a
chiral salt of the compound of formula VIIA;
[0060] (b) cooling the composition of step (a);
[0061] (c) isolating the chiral salt of the compound of formula
VIIA; and
[0062] (d) hydrolyzing the chiral salt of the compound of formula
VIIA to provide the enantiomerically enriched composition
comprising a compound of formula VIIA, or a salt thereof.
[0063] Also provided is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VB, or a salt thereof:
##STR00015##
[0064] wherein
[0065] R.sup.4 is hydrogen or C.sub.1-4 alkyl; and
[0066] R.sup.5 is hydrogen or C.sub.1-4 alkyl;
[0067] comprising isomerizing an enantiomerically enriched
composition of a compound of formula VIIB, or a salt thereof:
##STR00016##
[0068] Also provided is an enantiomerically enriched composition
comprising a compound selected from Table 1, or a salt thereof.
DETAILED DESCRIPTION
1. Definitions
[0069] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art. In case of conflict, the present
document, including definitions, will control. Preferred methods
and materials are described below, although methods and materials
similar or equivalent to those described herein can be used in
practice or testing of the present invention. All publications,
patent applications, patents and other references mentioned herein
are incorporated by reference in their entirety. The materials,
methods, and examples disclosed herein are illustrative only and
not intended to be limiting.
[0070] The terms "comprise(s)," "include(s)," "having," "has,"
"can," "contain(s)," and variants thereof, as used herein, are
intended to be open-ended transitional phrases, terms, or words
that do not preclude the possibility of additional acts or
structures. The singular forms "a," "an" and "the" include plural
references unless the context clearly dictates otherwise. The
present disclosure also contemplates other embodiments
"comprising," "consisting of" and "consisting essentially of," the
embodiments or elements presented herein, whether explicitly set
forth or not.
[0071] The modifier "about" used in connection with a quantity is
inclusive of the stated value and has the meaning dictated by the
context (for example, it includes at least the degree of error
associated with the measurement of the particular quantity). The
modifier "about" should also be considered as disclosing the range
defined by the absolute values of the two endpoints. For example,
the expression "from about 2 to about 4" also discloses the range
"from 2 to 4." The term "about" may refer to plus or minus 10% of
the indicated number. For example, "about 10%" may indicate a range
of 9% to 11%, and "about 1" may mean from 0.9-1.1. Other meanings
of "about" may be apparent from the context, such as rounding off,
so, for example "about 1" may also mean from 0.5 to 1.4.
[0072] The conjunctive term "or" includes any and all combinations
of one or more listed elements associated by the conjunctive term.
For example, the phrase "an apparatus comprising A or B" may refer
to an apparatus including A where B is not present, an apparatus
including B where A is not present, or an apparatus where both A
and B are present. The phrases "at least one of A, B, . . . and N"
or "at least one of A, B, . . . N, or combinations thereof" are
defined in the broadest sense to mean one or more elements selected
from the group comprising A, B, . . . and N, that is to say, any
combination of one or more of the elements A, B, . . . or N
including any one element alone or in combination with one or more
of the other elements which may also include, in combination,
additional elements not listed.
[0073] Definitions of specific functional groups and chemical terms
are described in more detail below. For purposes of this
disclosure, the chemical elements are identified in accordance with
the Periodic Table of the Elements, CAS version, Handbook of
Chemistry and Physics, 75th Ed., inside cover, and specific
functional groups are generally defined as described therein.
Additionally, general principles of organic chemistry, as well as
specific functional moieties and reactivity, are described in
Organic Chemistry, Thomas Sorrell, University Science Books,
Sausalito, 1999; Smith and March March's Advanced Organic
Chemistry, 5th Edition, John Wiley & Sons, Inc., New York,
2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods
of Organic Synthesis, 3rd Edition, Cambridge University Press,
Cambridge, 1987; the entire contents of each of which are
incorporated herein by reference.
[0074] The term "enantiomerically enriched" as used herein, refers
to a composition of a chiral substance whose enantiomeric ratio is
greater than 50:50, but less than 100:0. In certain embodiments,
the enantiomerically enriched composition has a % ee of greater
than about 25%, or greater than about 30%, or greater than about
35%, or greater than about 40%, or about 45%, or about 50%, or
about 55%, or greater than about 60%, or greater than about 65%, or
greater than about 70%, or greater than about 75%, or greater than
about 80%, or greater than about 85%, or greater than about 90%, or
greater than about 95%, or greater than about 97%, or greater than
about 99%, or about 25%, or about 30%, or about 35%, or about 40%,
or about 45%, or about 50%, or about 55%, or about 60%, or about
65%, or about 70%, or about 75%, or about 80%, or about 85%, or
about 90%, or about 95%, or about 97%, or about 99%, or about
100.
[0075] The term "alkyl" as used herein, means a straight or
branched, saturated hydrocarbon chain containing from 1 to 30
carbon atoms. The term "lower alkyl" or "C.sub.1-C.sub.6-alkyl"
means a straight or branched chain hydrocarbon containing from 1 to
6 carbon atoms. The term "C.sub.1-C.sub.3-alkyl" means a straight
or branched chain hydrocarbon containing from 1 to 3 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0076] The term "alkoxy" as used herein, refers to an alkyl group,
as defined herein, appended to the parent molecular moiety through
an oxygen atom. Representative examples of alkoxy include, but are
not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and
tert-butoxy.
[0077] The term "alkenyl" as used herein, means a hydrocarbon chain
containing from 2 to 30 carbon atoms with at least one
carbon-carbon double bond. The alkenyl group may be substituted or
unsubstituted. For example, the alkenyl group may be substituted
with an aryl group, such as a phenyl.
[0078] The term "alkynyl," as used herein, refers to straight or
branched monovalent hydrocarbyl groups having from 2 to 30 carbon
atoms, such as 2 to 20, or 2 to 10 carbon atoms and having at least
1 site of triple bond unsaturation. The term "alkyne" also includes
non-aromatic cycloalkyl groups of from 5 to 20 carbon atoms, such
as from 5 to 10 carbon atoms, having single or multiple rings and
having at least one triple bond. Examples of such alkynyl groups
include, but are not limited to acetylenyl (--C.ident.CH), and
propargyl (--CH.sub.2C.ident.CH), and cycloalkynyl moieties, such
as, but not limited to, substituted or unsubstituted cyclooctyne
moieties.
[0079] The term "alkoxyalkyl" as used herein, refers to an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein.
[0080] The term "alkylene", as used herein, refers to a divalent
group derived from a straight or branched chain hydrocarbon of 1 to
30 carbon atoms, for example, of 2 to 10 carbon atoms.
Representative examples of alkylene include, but are not limited
to, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.
[0081] The term "aryl" as used herein, refers to a phenyl group, or
bicyclic aryl or tricyclic aryl fused ring systems. Bicyclic fused
ring systems are exemplified by a phenyl group appended to the
parent molecular moiety and fused to a phenyl group. Tricyclic
fused ring systems are exemplified by a phenyl group appended to
the parent molecular moiety and fused to two other phenyl groups.
Representative examples of bicyclic aryls include, but are not
limited to, naphthyl. Representative examples of tricyclic aryls
include, but are not limited to, anthracenyl. The monocyclic,
bicyclic, and tricyclic aryls are connected to the parent molecular
moiety through any carbon atom contained within the rings, and can
be unsubstituted or substituted.
[0082] The term "cycloalkyl" as used herein, refers to a
carbocyclic ring system containing three to ten carbon atoms, zero
heteroatoms and zero double bonds. Representative examples of
cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclononyl and cyclodecyl. "Cycloalkyl" also includes carbocyclic
ring systems in which a cycloalkyl group is appended to the parent
molecular moiety and is fused to an aryl group as defined herein, a
heteroaryl group as defined herein, or a heterocycle as defined
herein.
[0083] The term "cycloalkenyl" as used herein, means a non-aromatic
monocyclic or multicyclic ring system containing at least one
carbon-carbon double bond and preferably having from 5-10 carbon
atoms per ring. Exemplary monocyclic cycloalkenyl rings include,
but are not limited to, cyclopentenyl, cyclohexenyl or
cycloheptenyl.
[0084] The term "cyclooctene" as used herein, refers to a
substituted or unsubstituted non-aromatic cyclic alkyl group of 8
carbon atoms, having a single ring with a double bond. Examples of
such cyclooctene groups include, but are not limited to,
substituted or unsubstituted trans-cyclooctene (TCO).
[0085] The term "fluoroalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five, six, seven
or eight hydrogen atoms are replaced by fluorine. Representative
examples of fluoroalkyl include, but are not limited to,
2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl,
difluoromethyl, pentafluoroethyl, and trifluoropropyl such as
3,3,3-trifluoropropyl.
[0086] The term "alkoxyfluoroalkyl" as used herein, refers to an
alkoxy group, as defined herein, appended to the parent molecular
moiety through a fluoroalkyl group, as defined herein.
[0087] The term "fluoroalkoxy" as used herein, means at least one
fluoroalkyl group, as defined herein, is appended to the parent
molecular moiety through an oxygen atom. Representative examples of
fluoroalkyloxy include, but are not limited to, difluoromethoxy,
trifluoromethoxy and 2,2,2-trifluoroethoxy.
[0088] The term "halogen" or "halo" as used herein, means Cl, Br,
I, or F.
[0089] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five, six, seven
or eight hydrogen atoms are replaced by a halogen.
[0090] The term "haloalkoxy" as used herein, means at least one
haloalkyl group, as defined herein, is appended to the parent
molecular moiety through an oxygen atom.
[0091] The term "heteroalkyl" as used herein, means an alkyl group,
as defined herein, in which one or more of the carbon atoms has
been replaced by a heteroatom selected from S, Si, O, P and N. The
heteroatom may be oxidized. Representative examples of heteroalkyls
include, but are not limited to, alkyl ethers, secondary and
tertiary alkyl amines, and alkyl sulfides.
[0092] The term "heteroaryl" as used herein, refers to an aromatic
monocyclic ring or an aromatic bicyclic ring system or an aromatic
tricyclic ring system. The aromatic monocyclic rings are five or
six membered rings containing at least one heteroatom independently
selected from the group consisting of N, O and S (e.g. 1, 2, 3, or
4 heteroatoms independently selected from O, S, and N). The five
membered aromatic monocyclic rings have two double bonds and the
six membered six membered aromatic monocyclic rings have three
double bonds. The bicyclic heteroaryl groups are exemplified by a
monocyclic heteroaryl ring appended to the parent molecular moiety
and fused to a monocyclic cycloalkyl group, as defined herein, a
monocyclic aryl group, as defined herein, a monocyclic heteroaryl
group, as defined herein, or a monocyclic heterocycle, as defined
herein. The tricyclic heteroaryl groups are exemplified by a
monocyclic heteroaryl ring appended to the parent molecular moiety
and fused to two of a monocyclic cycloalkyl group, as defined
herein, a monocyclic aryl group, as defined herein, a monocyclic
heteroaryl group, as defined herein, or a monocyclic heterocycle,
as defined herein. Representative examples of monocyclic heteroaryl
include, but are not limited to, pyridinyl (including pyridin-2-yl,
pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, thienyl,
furyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, and
2-oxo-1,2-dihydropyridinyl. Representative examples of bicyclic
heteroaryl include, but are not limited to, chromenyl,
benzothienyl, benzodioxolyl, benzotriazolyl, quinolinyl,
thienopyrrolyl, thienothienyl, imidazothiazolyl, benzothiazolyl,
benzofuranyl, indolyl, quinolinyl, imidazopyridine,
benzooxadiazolyl, and benzopyrazolyl. Representative examples of
tricyclic heteroaryl include, but are not limited to,
dibenzofuranyl and dibenzothienyl. The monocyclic, bicyclic, and
tricyclic heteroaryls are connected to the parent molecular moiety
through any carbon atom or any nitrogen atom contained within the
rings, and can be unsubstituted or substituted.
[0093] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic heterocycle, a bicyclic heterocycle, or a
tricyclic heterocycle. The monocyclic heterocycle is a three-,
four-, five-, six-, seven-, or eight-membered ring containing at
least one heteroatom independently selected from the group
consisting of O, N, and S. The three- or four-membered ring
contains zero or one double bond, and one heteroatom selected from
the group consisting of O, N, and S. The five-membered ring
contains zero or one double bond and one, two or three heteroatoms
selected from the group consisting of O, N and S. The six-membered
ring contains zero, one or two double bonds and one, two, or three
heteroatoms selected from the group consisting of O, N, and S. The
seven- and eight-membered rings contains zero, one, two, or three
double bonds and one, two, or three heteroatoms selected from the
group consisting of O, N, and S. Representative examples of
monocyclic heterocycles include, but are not limited to,
azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,
1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
1,3-dimethylpyrimidine-2,4(1H,3H)-dione, imidazolinyl,
imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl,
oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl,
pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,
tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,
1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl,
thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine
sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is
a monocyclic heterocycle fused to a phenyl group, or a monocyclic
heterocycle fused to a monocyclic cycloalkyl, or a monocyclic
heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic
heterocycle fused to a monocyclic heterocycle, or a spiro
heterocycle group, or a bridged monocyclic heterocycle ring system
in which two non-adjacent atoms of the ring are linked by an
alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene
bridge of two, three, or four carbon atoms. Representative examples
of bicyclic heterocycles include, but are not limited to,
benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline,
2-azaspiro[3.3]heptan-2-yl, azabicyclo[2.2.1]heptyl (including
2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl,
isoindolinyl, octahydrocyclopenta[c]pyrrolyl,
octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic
heterocycles are exemplified by a bicyclic heterocycle fused to a
phenyl group, or a bicyclic heterocycle fused to a monocyclic
cycloalkyl, or a bicyclic heterocycle fused to a monocyclic
cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic
heterocycle, or a bicyclic heterocycle in which two non-adjacent
atoms of the bicyclic ring are linked by an alkylene bridge of 1,
2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or
four carbon atoms. Examples of tricyclic heterocycles include, but
are not limited to, octahydro-2,5-epoxypentalene,
hexahydro-2H-2,5-methanocyclopenta[b]furan,
hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane
(1-azatricyclo[3.3.1.13,7]decane), and oxaadamantane
(2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and
tricyclic heterocycles are connected to the parent molecular moiety
through any carbon atom or any nitrogen atom contained within the
rings, and can be unsubstituted or substituted.
[0094] The term "hydroxyl" as used herein, means an --OH group.
[0095] The term "hydroxyalkyl" as used herein, means an alkyl
group, as defined herein, in which one, two, three, four, five,
six, seven or eight hydrogen atoms are replaced by a hydroxyl
group.
[0096] In some instances, the number of carbon atoms in a
hydrocarbyl substituent (e.g., alkyl or cycloalkyl) is indicated by
the prefix "C.sub.x-C.sub.y-" or "C.sub.x-y," wherein x is the
minimum and y is the maximum number of carbon atoms in the
substituent. Thus, for example, "C.sub.1-C.sub.3-alkyl" and
"C.sub.1-3alkyl" refer to an alkyl substituent containing from 1 to
3 carbon atoms. The two conventions "C.sub.x-C.sub.y-" and
"C.sub.x-y" are used interchangeably and have the same meaning.
[0097] The term "substituted" refers to a group that may be further
substituted with one or more non-hydrogen substituent groups.
Substituent groups include, but are not limited to, halogen,
.dbd.O, .dbd.S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl,
fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy,
heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy,
hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy,
benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,
sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,
arylsulfonyl, aminosulfonyl, sulfinyl, --COOH, ketone, amide,
carbamate, and acyl.
[0098] The term "therapeutic agent" refers to an agent capable of
treating and/or ameliorating a condition or disease, or one or more
symptoms thereof, in a subject. Therapeutic agents of the present
disclosure also include prodrug forms of therapeutic agents.
[0099] The term "diagnostic agent" refers to agents that assist in
diagnosing conditions or diseases. Representative diagnostic agents
include imaging agents such as paramagnetic agents, optical probes,
radionuclides, and the like. Paramagnetic agents are imaging agents
that are magnetic under an externally applied field. Examples of
paramagnetic agents include, but are not limited to, iron particles
including iron nanoparticles and iron microparticles. Optical
probes are fluorescent compounds that can be detected by excitation
at one wavelength of radiation and detection at a second,
different, wavelength of radiation. Optical probes of the present
disclosure include, but are not limited to, Cy5.5, Alexa 680, Cy5,
DiD (1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine
perchlorate) and DiR
(1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide).
Other optical probes include quantum dots. Radionuclides are
elements that undergo detectable radioactive decay. Radionuclides
useful in embodiments of the present disclosure include, but are
not limited to, .sup.3H, .sup.11C, .sup.13N, .sup.18F, .sup.19F,
.sup.60Co, .sup.64Cu, .sup.67Cu, .sup.68Ga, .sup.82Rb, .sup.90Sr,
.sup.90Y, .sup.99TC, .sup.99mTc, .sup.111In, .sup.123I, .sup.124I,
.sup.125I, .sup.129I, .sup.131I, .sup.137Cs, .sup.177Lu,
.sup.186Re, .sup.188Re, .sup.211At, Rn, Ra, Th, U, Pu and
.sup.241Am.
[0100] The term "contacting" or "contact" refers to the process of
bringing into contact at least two distinct species such that they
can interact with each other, such as in a non-covalent or covalent
binding interaction or binding reaction. It should be appreciated,
however, the resulting complex or reaction product can be produced
directly from an interaction or a reaction between the added
reagents or from an intermediate from one or more of the added
reagents or moieties, which can be produced in the contacting
mixture.
[0101] The term "leaving group" refers to an atom (or a group of
atoms) with electron withdrawing ability that can be displaced as a
stable species, taking with it the bonding electrons. Examples of
suitable leaving groups include halides (e.g., Br, Cl, I),
sulfonate esters (e.g., triflate, mesylate, tosylate, and
brosylate), and nitrophenols.
[0102] The term "physiological conditions" is meant to encompass
those conditions compatible with living cells, e.g., predominantly
aqueous conditions of a temperature, pH, salinity, etc. that are
compatible with living cells.
[0103] The term "chiral base" is meant to encompass a chiral
compound having at least one stereocenter and at least one nitrogen
atom. The chiral base can be synthesized using methods known in the
art or purchased from commercial sources (e.g., Sigma Aldrich).
Exemplary chiral bases include, but are not limited to,
L-(-)-.alpha.-Amino-.epsilon.-caprolactam hydrochloride,
(R)-(-)-1-Amino-2-propanol, (S)-(+)-1-Amino-2-propanol, L-Aspartic
acid, cis-(1S,2R)-(-)-2-(Benzylamino)cyclohexane methanol,
(S)--N-Benzyl-1-(1-naphthyl)ethylamine hydrochloride,
(-)-1,4-Bis-O-(4-chlorobenzyl)-L-threitol,
(1R,2R)-1,2-Bis(2-hydroxyphenyl)ethylenediamine,
(1S,2S)-1,2-Bis(2-hydroxyphenyl)ethylenediamine,
(+)-Bis[(R)-1-phenylethyl]amine hydrochloride,
N,N-Bis[(S)-(-)-1-phenylethyl]phthalamic acid,
(R)-(+)-1-(4-Bromophenyl)ethylamine,
(S)-(-)-1-(4-Bromophenyl)ethylamine,
(R)-4-Chloro-.alpha.-methylbenzylamine,
(S)-4-Chloro-.alpha.-methylbenzylamine, Cinchonidine,
(+)-Cinchonine, (R)-(+)-N,.alpha.-Dimethylbenzylamine,
(S)-(-)-N,.alpha.-Dimethylbenzylamine,
(R)-(+)-N,N-Dimethyl-1-phenylethylamine,
(S)-(-)-N,N-Dimethyl-1-phenylethylamine,
(R)-5,5-Dimethyl-6-phenyl-3,4,5,6-tetrahydropyrimidine,
(S)-5,5-Dimethyl-6-phenyl-3,4,5,6-tetrahydropyrimidine,
(R)-(-)-3,5-Dinitro-N-(1-phenylethyl)benzamide,
(S)-(+)-3,5-Dinitro-N-(1-phenylethyl)benzamide,
(1R,2S)-(-)-Ephedrine, D-Glutamic acid, L-Glutamic acid,
(R)-(+)-.alpha.-Methylbenzylamine,
(S)-(-)-.alpha.-Methylbenzylamine,
(R)-.alpha.-Methyl-4-nitrobenzylaminehydrochloride,
(S)-.alpha.-Methyl-4-nitrobenzylaminehydrochloride,
(R)-(+)-.alpha.-Methyl-4-pyridinemethanol,
(S)-(-)-.alpha.-Methyl-4-pyridinemethanol,
(S)-(-)-1-(2-Naphthyl)ethylamine,
(S)-(-)-N-[1-(1-Naphthyl)ethyl]succinamic acid,
(R)-(+)-N-(1-Phenylethyl)phthalamic acid,
(S)-(-)-N-(1-Phenylethyl)phthalamic acid,
(R)-(+)-N-(1-Phenylethyl)succinamic acid,
(S)-(-)-N-(1-Phenylethyl)succinamic acid, Quinine, D-Valine, and
L-Valine.
[0104] For compounds described herein, groups and substituents
thereof may be selected in accordance with permitted valence of the
atoms and the substituents, such that the selections and
substitutions result in a stable compound, e.g., which does not
spontaneously undergo transformation such as by rearrangement,
cyclization, elimination, etc.
[0105] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within the invention.
The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges, and are also
encompassed within the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in the invention.
[0106] For the recitation of numeric ranges herein, each
intervening number there between with the same degree of precision
is explicitly contemplated. For example, for the range of 6-9, the
numbers 7 and 8 are contemplated in addition to 6 and 9, and for
the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,
6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
[0107] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable sub-combination.
All combinations of the embodiments pertaining to the invention are
specifically embraced by the present invention and are disclosed
herein just as if each and every combination was individually and
explicitly disclosed, to the extent that such combinations embrace
subject matter that are, for example, compounds that are stable
compounds (i.e., compounds that can be made, isolated,
characterized, and tested for biological activity). In addition,
all sub-combinations of the various embodiments and elements
thereof (e.g., elements of the chemical groups listed in the
embodiments describing such variables) are also specifically
embraced by the present invention and are disclosed herein just as
if each and every such sub-combination was individually and
explicitly disclosed herein.
2. Processes
[0108] The processes described herein provide functionalized
payloads which have improved aqueous solubility compared with
payloads linked to an unsubstituted cyclooctene. The functionalized
payloads can be used as reagents in bioorthogonal conjugation or
click reactions, and have use in various applications in the fields
of chemistry, chemical biology, molecular diagnostics, and
medicine, where they can be used to facilitate the selective
manipulation of molecules, cells, particles and surfaces, and the
tagging and tracking of biomolecules in vitro and in vivo. The
processes described herein are performed using suitable reactions
conditions and optionally one or more protecting groups as
needed.
[0109] The term "reaction conditions" is intended to refer to the
physical and/or environmental conditions under which a chemical
reaction proceeds. Examples of reaction conditions include, but are
not limited to, one or more of following: reaction temperature,
solvent, pH, pressure, reaction time, mole ratio of reactants, the
presence of a base or acid, one or more protecting groups, or
catalyst, radiation, etc. Reaction conditions may be named after
the particular chemical reaction in which the conditions are
employed, such as, coupling conditions, hydrogenation conditions,
acylation conditions, reduction conditions, etc. Reaction
conditions for most reactions are generally known to those skilled
in the art or can be readily obtained from the literature.
Exemplary reaction conditions sufficient for performing the
chemical transformations provided herein can be found throughout,
and in particular, the examples below. It is also contemplated that
the reaction conditions can include reagents in addition to those
listed in the specific reaction.
[0110] The term "protecting group" refers to those groups intended
to protect a given atom or functional group against undesirable
reactions during synthetic procedures and includes, but is not
limited to, silyl ethers, such as 2-(trimethylsilyl)ethoxymethyl
(SEM) ether, or alkoxymethyl ethers, such as methoxymethyl (MOM)
ether, tert-butoxymethyl (BUM) ether, benzyloxymethyl (BOM) ether
or methoxyethoxymethyl (MEM) ether. Additional protecting groups
include, tert-butyl, acetyl, benzyl, benzyloxycarbonyl
(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC),
trifluoroacetyl, and the like. Certain protecting groups may be
preferred over others due to their convenience or relative ease of
removal, or due to their stereospecific effects in subsequent steps
of the process. Additional suitable amino protecting groups are
taught in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Fifth Edition, Wiley, New York, 2014, and
references cited therein which are all incorporated by reference in
its entirety.
[0111] In one embodiment, the present disclosure provides a process
for preparing a compound of formula I, or a salt thereof:
##STR00017##
[0112] wherein
[0113] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0114] n is 0, 1, 2, 3 or 4;
[0115] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy;
[0116] D is a payload moiety; and
[0117] R.sup.4 is hydrogen or C.sub.1-4 alkyl;
[0118] comprising contacting a compound of formula II:
##STR00018##
[0119] with HO--R.sup.4, an optionally substituted heterocyclyl or
an amino acid moiety, or a salt thereof, and a compound of formula
III:
##STR00019##
[0120] wherein each R.sup.3 is independently C.sub.1-4 alkyl, in an
organic solvent in the presence of a base.
[0121] In one embodiment, the present disclosure provides a process
for preparing a compound of formula I, or a salt thereof:
##STR00020##
[0122] wherein
[0123] R.sup.1 is an amino acid moiety;
[0124] n is 0, 1, 2, 3 or 4;
[0125] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy; and
[0126] D is a payload moiety;
[0127] comprising contacting a compound of formula II:
##STR00021##
[0128] with an amino acid moiety, or a salt thereof, and a compound
of formula III:
##STR00022##
[0129] wherein each R.sup.3 is independently C.sub.1-4 alkyl, in an
organic solvent in the presence of a base.
[0130] In one embodiment, the present disclosure provides a process
for preparing a compound of formula I, or a salt thereof:
##STR00023##
[0131] wherein
[0132] R.sup.1 is selected from the group consisting of G.sup.1,
OH, --NR.sup.1c--C.sub.1-4alkylene-G.sup.1,
--NR.sup.1c--C.sub.1-4alkylene-N(R.sup.1d).sub.2,
--N(R.sup.1c)CHR.sup.1cCO.sub.2H,
--N(R.sup.1c)--C.sub.1-6alkylene-CO.sub.2H,
--N(R.sup.1f)--C.sub.2-4alkylene-(N(C.sub.1-4alkylene-CO.sub.2H)--C.sub.2-
-4 alkylene).sub.m-N(C.sub.1-4alkylene-CO.sub.2H).sub.2,
--N(R.sup.1c)CHR.sup.1cC(O)OC.sub.1-6alkyl,
--N(R.sup.1c)--C.sub.1-6 alkylene-C(O)OC.sub.1-6 alkyl, and
--N(R.sup.1f)--C.sub.2-4
alkylene-(N(C.sub.1-4alkylene-C(O)OC.sub.1-6 alkyl)-C.sub.2-4
alkylene).sub.m-N(C.sub.1-4alkylene-C(O)OC.sub.1-6
alkyl).sub.2;
[0133] R.sup.1c and R.sup.1d, at each occurrence, are independently
hydrogen or C.sub.1-4alkyl;
[0134] R.sup.1e is --C.sub.1-4alkylene-CO.sub.2H,
--C.sub.1-4alkylene-CONH.sub.2, or --C.sub.1-4alkylene-OH;
[0135] R.sup.1f is hydrogen, C.sub.1-6 alkyl, or
C.sub.1-4alkylene-CO.sub.2H;
[0136] G.sup.1 is an optionally substituted heterocyclyl.
[0137] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy;
[0138] D is a payload moiety;
[0139] n is 0, 1, 2, 3 or 4; and
[0140] m is 0, 1, 2, or 3;
[0141] comprising contacting a compound of formula II:
##STR00024##
[0142] with a suitable reagent and a compound of formula III:
##STR00025##
[0143] wherein each R.sup.3 is independently C.sub.1-4 alkyl, in an
organic solvent in the presence of a base.
[0144] In certain embodiments, R.sup.1 is selected from the group
consisting of G.sup.1, OH, --NR.sup.1c--C.sub.1-4alkylene-G.sup.1,
--NR.sup.1c--C.sub.1-4 alkylene-N(R.sup.1d).sub.2,
--N(R.sup.1c)CHR.sup.1eCO.sub.2H, --N(R.sup.1c)CH.sub.2CO.sub.2H,
and
--N(R.sup.1f)--CH.sub.2CH.sub.2--(N(CH.sub.2CO.sub.2H)CH.sub.2CH.sub.2).s-
ub.m--N(CH.sub.2CO.sub.2H).sub.2;
[0145] R.sup.1e is --C.sub.1-4alkylene-CO.sub.2H;
[0146] R.sup.1f is hydrogen or --C.sub.1-4alkylene-CO.sub.2H;
[0147] G.sup.1 is a 4- to 8-membered monocyclic heterocyclyl
containing a first nitrogen and optionally one additional
heteroatom selected from nitrogen, oxygen, and sulfur, G.sup.1
being attached at the first nitrogen and optionally substituted
with 1-4 substituents independently selected from the group
consisting of
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, halo, cyano, OH, --OC.sub.1-4
alkyl, and oxo; and
[0148] m is 0, 1, or 2.
[0149] In certain embodiments, R.sup.1 is an amino acid moiety.
[0150] In certain embodiments, the compound of formula III is
N,O-bis(trimethylsilyl)acetamide.
[0151] In certain embodiments, the organic solvent comprises DMF,
DCM or a mixture thereof.
[0152] In certain embodiments, the base comprises an organic base.
In certain embodiments, the base comprises an amine base. In
certain embodiments, the base comprises DIPEA.
[0153] In certain embodiments, the contacting comprises stirring at
room temperature for about 24 hours.
[0154] In certain embodiments, the process further comprises
preparing the compound of formula II by reacting a compound of
formula IV:
##STR00026##
[0155] with a payload moiety, or a salt thereof, in an organic
solvent in the presence of a base.
[0156] In certain embodiments, the organic solvent comprises DMF,
DCM or a mixture thereof.
[0157] In certain embodiments, the base comprises an organic base.
In certain embodiments, the base comprises an amine base. In
certain embodiments, the base comprises DIPEA.
[0158] In certain embodiments, the contacting comprises stirring at
room temperature for about 1 to 2 hours.
[0159] In certain embodiments, the compound of formula I is
represented by formula IA:
##STR00027##
[0160] wherein
[0161] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0162] R.sup.4 is hydrogen or C.sub.1-4 alkyl;
[0163] R.sup.5 is hydrogen or C.sub.1-4 alkyl; and
[0164] D is a payload moiety;
[0165] and the compound of formula II is represented by formula
IIA:
##STR00028##
[0166] In certain embodiments, the compound of formula I is
represented by formula IA:
##STR00029##
[0167] wherein
[0168] R.sup.1 is an amino acid moiety;
[0169] R.sup.5 is hydrogen or C.sub.1-4alkyl; and
[0170] D is a payload moiety;
[0171] and the compound of formula II is represented by formula
IIA:
##STR00030##
[0172] In certain embodiments, the compound of formula IV is
represented by formula IVA:
##STR00031##
[0173] Also provided herein is a process of preparing a compound of
formula X, or a salt thereof:
##STR00032##
[0174] wherein
[0175] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0176] n is 0, 1, 2, 3 or 4;
[0177] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy; and R.sup.4 is hydrogen or
C.sub.1-4alkyl;
[0178] comprising contacting a compound of formula IV:
##STR00033##
[0179] with HO--R.sup.4, an optionally substituted heterocyclyl or
an amino acid moiety, or a salt thereof, and a compound of formula
III:
##STR00034##
[0180] wherein each R.sup.3 is independently C.sub.1-4alkyl, in an
organic solvent in the presence of a base.
[0181] Also provided herein is a process of preparing a compound of
formula X, or a salt thereof:
##STR00035##
[0182] wherein
[0183] R.sup.1 is an amino acid moiety;
[0184] n is 0, 1, 2, 3 or 4;
[0185] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy; and
[0186] comprising contacting a compound of formula IV:
##STR00036##
[0187] with an amino acid, or a salt thereof, and a compound of
formula III:
##STR00037##
[0188] wherein each R.sup.3 is independently C.sub.1-4 alkyl, in an
organic solvent in the presence of a base.
[0189] In certain embodiments, the compound of formula III is
N,O-bis(trimethylsilyl)acetamide.
[0190] In certain embodiments, the organic solvent comprises DMF,
DCM or a mixture thereof.
[0191] In certain embodiments, the base comprises an organic base.
In certain embodiments, the base comprises an amine base. In
certain embodiments, the base comprises DIPEA.
[0192] In certain embodiments, the contacting comprises stirring at
room temperature for about 24 hours.
[0193] In certain embodiments, the compound of formula X is
represented by formula XA:
##STR00038##
[0194] and the compound of formula IV is represented by formula
IVA:
##STR00039##
[0195] wherein R.sup.1 is as defined herein, and R.sup.5 is
hydrogen or C.sub.1-4 alkyl.
[0196] In certain embodiments, provided is a process for preparing
the compound of formula IV wherein R.sup.2 and n are as defined
herein, or a salt thereof, comprising contacting a compound of
formula V, or a salt thereof:
##STR00040##
with N,N'-disuccinimidylcarbonate in an organic solvent in the
presence of a base.
[0197] In certain embodiments, the organic solvent comprises
acetonitrile. In certain embodiments, the organic solvent comprises
dry acetonitrile.
[0198] In certain embodiments, the base comprises an organic base.
In certain embodiments, the base comprises an amine base. In
certain embodiments, the base comprises DIPEA.
[0199] In certain embodiments, the contacting comprises stirring at
room temperature.
[0200] In certain embodiments, the compound of formula V is
represented by formula VA:
##STR00041##
[0201] wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl and R.sup.5
is hydrogen or C.sub.1-4 alkyl.
[0202] Also provided is a process of preparing a compound of
formula I, or a salt thereof:
##STR00042##
[0203] wherein
[0204] R.sup.1 is selected from the group consisting of --OR.sup.4,
optionally substituted heterocyclyl, and an amino acid moiety;
[0205] n is 0, 1, 2, 3 or 4;
[0206] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy;
[0207] D is a payload moiety; and
[0208] R.sup.4 is hydrogen or C.sub.1-4 alkyl;
[0209] comprising contacting a compound of formula X, or a salt
thereof:
##STR00043##
[0210] with a payload moiety, or a salt thereof, in an organic
solvent in the presence of a base.
[0211] Also provided is a process of preparing a compound of
formula I, or a salt thereof:
##STR00044##
[0212] wherein
[0213] R.sup.1 is an amino acid moiety;
[0214] n is 0, 1, 2, 3 or 4;
[0215] each R.sup.2 is independently C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, and C.sub.1-4 alkoxy; and
[0216] D is a payload moiety;
[0217] comprising contacting a compound of formula X, or a salt
thereof:
##STR00045##
[0218] with a payload moiety, or a salt thereof, in an organic
solvent in the presence of a base.
[0219] In certain embodiments, the organic solvent comprises DMF,
DCM or a mixture thereof.
[0220] In certain embodiments, the base comprises an organic base.
In certain embodiments, the base comprises an amine base. In
certain embodiments, the base comprises DIPEA.
[0221] In certain embodiments, the contacting comprises stirring at
room temperature for about 1 to 2 hours.
[0222] In certain embodiments, the compound of formula I is
represented by formula IA:
##STR00046##
[0223] and the compound of formula X is represented by formula
XA:
##STR00047##
[0224] wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl.
[0225] Also provided herein is a process of preparing a composition
comprising a compound of formula IV, or a salt thereof:
##STR00048##
[0226] wherein
[0227] n is 0, 1, 2, 3, or 4; and
[0228] each R.sup.2 independently hydrogen or C.sub.1-4 alkyl;
[0229] comprising contacting one equivalent of a compound of
formula V, or a salt thereof:
##STR00049##
[0230] with 3-5 equivalents of N,N'-disuccinimidylcarbonate in
15-25 volumes of an anhydrous organic solvent in the presence of a
base at a temperature from 15-30.degree. C. for 5-10 hours.
[0231] In certain embodiments, the process further comprises adding
the composition comprising a compound of formula IV to 40-60
volumes of water at room temperature to form an aqueous product
mixture.
[0232] In certain embodiments, the process further comprises
isolating a solid formed in the aqueous product mixture.
[0233] In certain embodiments, the process further comprises
triturating the solid in acetonitrile at a temperature of from
about 30 to about 50.degree. C. to form a triturated solid.
[0234] In certain embodiments, the process further comprises
isolating the triturated solid.
[0235] In certain embodiments, the anhydrous organic solvent is
anhydrous acetonitrile.
[0236] In certain embodiments, the base is a trialkylamine
base.
[0237] In certain embodiments, the base is
diisopropylethylamine.
[0238] In certain embodiments, the compound of formula IV is
represented by formula IVA:
##STR00050##
[0239] and the compound of formula V is represented by formula
VA:
##STR00051##
[0240] wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl and R.sup.5
is hydrogen or C.sub.1-4 alkyl.
[0241] Also provided herein is a process for resolving a
composition comprising one or more stereoisomers of a compound of
formula VI, or a salt thereof:
##STR00052##
[0242] wherein
[0243] n is 0, 1, 2, 3, or 4;
[0244] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy;
[0245] comprising the steps of:
[0246] (a) contacting a composition comprising one or more
stereoisomers of formula VI with a chiral base to provide a chiral
salt of the compound of formula VI;
[0247] (b) cooling the composition of step (a);
[0248] (c) isolating the chiral salt of the compound of formula VI;
and
[0249] (d) hydrolyzing the chiral salt of the compound of formula
VI to provide the enantiomerically enriched composition comprising
a compound of formula VI, or a salt thereof.
[0250] In certain embodiments, the chiral base is cinchonidine.
[0251] In certain embodiments, the contacting of step (a) is
performed in a solvent selected from acetone/water or
acetone/isopropyl alcohol.
[0252] In certain embodiments, the cooling of step (b) is performed
at a temperature at or below about 15.degree. C.
[0253] In certain embodiments, the cooling of step (b) is at a
temperature of from about 10 to about 15.degree. C.
[0254] In certain embodiments, the cooling of step (b) is
maintained for at least about 8 hours.
[0255] In certain embodiments, the isolating of step (c) is via
filtration.
[0256] In certain embodiments, the process further comprises
dissolving the chiral salt of the compound of formula VI obtained
from step (c) in a suitable solvent, and repeating steps (b) and
(c) prior to step (d).
[0257] In certain embodiments, the process further comprises the
steps of dissolving the chiral salt of the compound of formula VI
obtained from step (c) in a suitable solvent, and repeating steps
(b) and (c) two, three, four, five or six times prior to step
(d).
[0258] In certain embodiments, the compound of formula VI is
represented by formula VIA:
##STR00053##
[0259] wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl.
[0260] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VII, or a salt thereof:
##STR00054##
[0261] wherein
[0262] n is 0, 1, 2, 3 or 4;
[0263] each R.sup.2 is independently C.sub.1-4alkyl,
C.sub.1-4haloalkyl, and C.sub.1-4alkoxy; and
[0264] R.sup.4 is independently hydrogen or C.sub.1-4 alkyl;
[0265] comprising sequentially contacting an enantiomerically
enriched composition of a compound of formula VI, or a salt
thereof:
##STR00055##
[0266] with: (i) a solution comprising KI and I.sub.2, (ii) a base,
and (iii) a hydrolyzing composition comprising a base and a
compound of formula R.sup.4--OH, to provide the enantiomerically
enriched composition of a compound of formula VII, or a salt
thereof.
[0267] Also provided herein is a process of claim 34, wherein the
compound of formula VII is represented by formula VIIA:
##STR00056##
[0268] and the compound of formula VI is represented by formula
VIA:
##STR00057##
[0269] wherein R.sup.5 is hydrogen or C.sub.1-4alkyl.
[0270] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VIIB, or a salt thereof:
##STR00058##
[0271] wherein R.sup.4 is hydrogen or C.sub.1-4 alkyl R.sup.5 is
hydrogen or C.sub.1-4 alkyl, comprising hydrolyzing an
enantiomerically enriched composition of a compound of formula IXB,
or a salt thereof:
##STR00059##
[0272] with a hydrolyzing composition comprising a base and a
compound of formula R.sup.4--OH, to provide the enantiomerically
enriched composition of a compound of formula VIIB, or a salt
thereof.
[0273] Also provided herein is a process for resolving a
composition comprising one or more stereoisomers of a compound of
formula VIIA, or a salt thereof:
##STR00060##
[0274] wherein
[0275] R.sup.5 is hydrogen or C.sub.1-4alkyl, comprising the steps
of:
[0276] (a) contacting a composition comprising one or more
stereoisomers of formula VIIA with a chiral base to provide a
chiral salt of the compound of formula VIIA;
[0277] (b) cooling the composition of step (a);
[0278] (c) isolating the chiral salt of the compound of formula
VIIA; and
[0279] (d) hydrolyzing the chiral salt of the compound of formula
VIIA to provide the enantiomerically enriched composition
comprising a compound of formula VIIA, or a salt thereof.
[0280] In certain embodiments, the chiral base is
(R)-1-amino-2-propanol. In certain embodiments, the chiral base is
L-phenylalaninol. In certain embodiments, the chiral base is
(S)-phenylglycinol. In certain embodiments, the chiral base is
(S)-diphenyl-2-pyrrolidine methanol.
[0281] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula IXB, or a salt thereof:
##STR00061##
[0282] wherein R.sup.5 is hydrogen or C.sub.1-4alkyl, comprising
contacting an enantiomerically enriched composition of a compound
of formula VIIIB, or a salt thereof:
##STR00062##
[0283] with a base to provide the enantiomerically enriched
composition of a compound of formula IXB, or a salt thereof.
[0284] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VIIIB, or a salt thereof:
##STR00063##
[0285] wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl, comprising
contacting an enantiomerically enriched composition of a compound
of formula VIB, or a salt thereof:
##STR00064##
[0286] with a solution comprising KI and I.sub.2 to provide the
enantiomerically enriched composition of a compound of formula
VIIIB, or a salt thereof.
[0287] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VIIB, or a salt thereof:
##STR00065##
[0288] wherein
[0289] R.sup.4 is hydrogen or C.sub.1-4alkyl; and
[0290] R.sup.5 is hydrogen or C.sub.1-4alkyl;
[0291] comprising the steps of:
[0292] (a) contacting an enantiomerically enriched composition of a
compound of formula VIB, or a salt thereof:
##STR00066##
with a solution comprising KI and I.sub.2 to provide an
enantiomerically enriched composition of a compound of formula
VIIIB, or a salt thereof:
##STR00067##
[0293] (b) contacting the enantiomerically enriched composition of
a compound of formula VIIIB with a base to provide an
enantiomerically enriched composition of a compound of formula IXB,
or a salt thereof:
##STR00068##
[0294] (c) hydrolyzing the enantiomerically enriched composition of
a compound of formula IXB, or a salt thereof, with a hydrolyzing
composition comprising a base and a compound of formula
R.sup.4--OH, to provide the enantiomerically enriched composition
of a compound of formula VIIB, or a salt thereof.
[0295] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula VB, or a salt thereof:
##STR00069##
[0296] wherein
[0297] R.sup.4 is hydrogen or C.sub.1-4alkyl; and
[0298] R.sup.5 is hydrogen or C.sub.1-4alkyl;
[0299] comprising isomerizing an enantiomerically enriched
composition of a compound of formula VIIB, or a salt thereof:
##STR00070##
[0300] In certain embodiments, the isomerizing comprises exposing
the compound of formula VA to UV light.
[0301] In certain embodiments, when R.sup.4 is C.sub.1-4alkyl, the
process further comprises a hydrolyzing step to convert R.sup.4 to
hydrogen.
[0302] Also provided herein is a process for the preparation of an
enantiomerically enriched composition comprising a compound of
formula IVB, or a salt thereof:
##STR00071## [0303] wherein R.sup.5 is hydrogen or C.sub.1-4 alkyl,
comprising contacting an enantiomerically enriched composition of a
compound of formula VB, or a salt thereof:
##STR00072##
[0304] with N,N-disuccinimidyl carbonate (DSC) under conditions to
provide the enantiomerically enriched composition comprising a
compound of formula IVB.
[0305] In certain embodiments of any of the formulas described
herein, R.sup.1 is a glycine moiety. In certain embodiments of any
of the formulas described herein, R.sup.1 is glycine.
[0306] In certain embodiments of any of the formulas described
herein, n is 1.
[0307] In certain embodiments of any of the formulas described
herein, R.sup.2 is C.sub.1-4 alkyl. In certain embodiments of any
of the formulas described herein, R.sup.2 is methyl.
[0308] In certain embodiments of any of the formulas described
herein, R.sup.5 is methyl.
[0309] Amino Acid Moieties
[0310] The term "amino acid" refers to both natural and unnatural
amino acids. In certain embodiments, the amino acid moiety is a
natural amino acid. The natural amino acids comprise the twenty
proteinogenic amino acids encoded directly by triplet codons in the
genetic code, and include alanine (ala, A), arginine (arg, R),
asparagine (asn, N) aspartic acid (asp, D), cysteine (cys, C)
glutamine (gln, Q) glutamic acid (glu, E) glycine (gly, G)
histidine (his, H) isoleucine (ile, I) leucine (leu, L) lysine
(lys, K) methionine (met, M) phenylalanine (phe, F) proline (pro,
P) serine (ser, S) threonine (thr, T) tryptophan (trp, W) tyrosine
(tyr, Y) and valine (val, V).
[0311] The amino acid moiety may also comprise an unnatural amino
acid. In its broadest meaning, the term "amino acid moiety"
comprises any organic compound with an amine (--NH.sub.2) and a
carboxylic acid (--CO.sub.2H) functional group.
[0312] In certain embodiments, the amino acid moiety is selected
from the group consisting of
--NR.sup.1c--C.sub.1-4alkylene-optionally substituted heterocyclyl,
--NR.sup.1c--C.sub.1-4alkylene-N(R.sup.1d).sub.2,
--N(R.sup.1c)CHR.sup.1eCO.sub.2H,
--N(R.sup.1c)--C.sub.1-6alkylene-CO.sub.2H,
--N(R.sup.1f)--C.sub.2-4alkylene-(N(C.sub.1-4alkylene-CO.sub.2H)--C.sub.2-
-4 alkylene).sub.m-N(C.sub.1-4 alkylene-CO.sub.2H).sub.2,
--N(R.sup.1c)CHR.sup.1eC(O)OC.sub.1-6alkyl,
--N(R.sup.1c)--C.sub.1-6alkylene-C(O)OC.sub.1-6 alkyl, and
--N(R.sup.1f)--C.sub.2-4
alkylene-(N(C.sub.1-4alkylene-C(O)OC.sub.1-6 alkyl)-C.sub.2-4
alkylene).sub.m-N(C.sub.1-4 alkylene-C(O)OC.sub.1-6 alkyl).sub.2;
wherein
[0313] R.sup.1c and R.sup.1d are each independently hydrogen or
C.sub.1-4alkyl;
[0314] R.sup.1e is --C.sub.1-4alkylene-CO.sub.2H,
--C.sub.1-4alkylene-CONH.sub.2, or --C.sub.1-4alkylene-OH;
[0315] R.sup.1f is hydrogen, --C.sub.1-6 alkyl, or
--C.sub.1-4alkylene-CO.sub.2H; and
[0316] m is 0, 1, 2, or 3.
[0317] In certain embodiments, the amino acid moiety is glycine. In
certain embodiments, the amino acid moiety is alanine.
[0318] Payloads
[0319] As used herein, a "payload moiety" refers to a payload D
minus its nucleophilic group such as NH, NC.sub.1-4alkyl, O, or S
that attaches to a linker or minus its electrophilic group such as
C(O) that attaches to a linker, i.e., the remainder of the payload.
The term "payload", in general, refers to an agent for delivery to
a target site in a subject, and includes, but isn't limited to,
therapeutic agents, diagnostic agents, targeting agents, and the
like.
[0320] In some embodiments, the payload is a therapeutic agent,
such as an antibiotic agent, antifungal agent, antiviral agent,
anticancer agent, cardiovascular agent, CNS agent,
anti-inflammatory/anti-arthritic agent, anti-TB/anti-leprosy agent,
anti-histaminic/respiratory disorder agent, a corticosteroid agent,
immunosuppressant agent, or anti-ulcer agent. Particular
therapeutic agents include paclitaxel, doxorubicin, daunorubicin,
etoposide, irinotecan, SN-38, docetaxel, gemcitabine,
podophyllotoxin, carmustine, ixabepilone, patupilone, cyclosporin
A, rapamycin, amphotericin, vancomycin, daptomycin, doxycycline,
ceftriaxone, trimethoprim, sulfamethoxazole, acyclovir, nystatin,
amphotericin B, flucytosine, emtricitabine, gentamicin, colistin,
L-dopa, oseltamivir, cefalexin, 5-aminolevulinic acid, cysteine,
celecoxib, and nimodipine.
[0321] In certain embodiments, the payload moiety is an
anthracycline moiety, an auristatin moiety, a glycopeptide
antibiotic moiety, or a lipopeptide antibiotic moiety.
[0322] In certain embodiments, the payload moiety is a doxorubicin
moiety, daunorubicin moiety, monomethyl auristatin E moiety,
vancomycin moiety or daptomycin moiety.
[0323] In certain embodiments, D is an antibiotic agent, antifungal
agent, antiviral agent, anticancer agent, cardiovascular agent, CNS
agent, anti-inflammatory/anti-arthritic agent, anti-TB/anti-leprosy
agent, anti-histaminic/respiratory disorder agent, a corticosteroid
agent, immunosuppressant agent, or anti-ulcer agent.
[0324] In certain embodiments, D is an antibiotic. Suitable
antibiotics include, but are not limited to .beta.-lactams,
including penicillins and cephalosporins, such as thienamycins,
monobactams, .beta.-lactamade inhibitors and methoxypeniciuins;
aminoglycosides, including streptomycin, gentamicin, kanamycin,
tobramycin, amikacin, neomycin, ribostamycin, micronomicin and
astromicin; tetracyclines, including tetracycline, oxytetracycline,
chlortetracycline and doxycycline; chloramphenicols, including
chloramphenicol and thiamphenicol; macrolides, including
erythromycin, albomycin, erythromycin estolate, erythromycin
ethylsuccinate, azithromycin, acetylspiramycin, midecamycin and
josamycin; other antibiotics acting on Gram-positive bacteria, such
as lincomycin, clindamycin, vancomycin and bacitracin; other
antibiotics acting on Gram bacteria, such as polymyxin, fosfomycin,
ciramycin, cycloserine and rifampicin; antifungal antibiotics, such
as griseofulvin; anticancer antibiotics, such as mitomycin,
actinomycin D, bleomycin and Adriamycin; and immunosuppressive
antibiotics, such as cyclosporine.
[0325] In certain embodiments, D is an anticancer drug, an
anticoagulant, a microbial immunosuppressive drug, or an
anti-restenosis drug. The anticancer drug may be one or more
selected from methotrexate, purines, pyrimidines, plant alkaloids,
epothilones, triptolide compounds, antibiotics (notably actinomycin
D), hormones and antibodies. From among the plant alkaloids,
mention may notably be made of paclitaxel, doxorubicin, maytansin,
auristatin, calicheamycin, duocarmycin, tubulysin and camptothecin.
The anticoagulant may be one or more selected from heparin,
aspirin, hirudin, colchicine and platelet GPIIb/IIIa receptor
antagonists.
[0326] The platelet GPIIb/IIIa receptor antagonists may be one or
more selected from tirofiban, abciximab and eptifibatide. The
microbial immunosuppressive drug may be one or more selected from
cyclosporin A, tacrolimus and its analogues, despergualin,
mycophenolate esters, rapamycin and its derivatives, FR-900520
substance from Streptomyces strains, FR-900523 substance from
Streptomyces strains, daclizumab, pentanamide, kanglemycin C,
spergualin, prodigiosin-25C, tranilast, myriocin, cyclosporin C,
bredinin, mycophenolic acid, brefeldin A and ketosteroids. The
anti-restenosis drug may be one or more selected from batimastat,
metalloproteinase inhibitors, 17.beta.-estradiol, NO donors,
2-chlorodeoxyadeno sine, 2-deoxycoformycin, fingolimod,
mycophenolate sodium, ISATX247 (a cyclosporin A derivative),
elsibucol, daclizumab, basiliximab, anti-thymocyte globulin,
everolimus, methotrexate, neoral, cyclophosphamide, brequinar
sodium, leflunomide and mizoribine.
[0327] In certain embodiments, D is an anticancer drug. Exemplary
anti-cancer drugs include, but are not limited to, Abiraterone
Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel
Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC,
AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab
Emtansine, Adriamycin (Doxorubicin Hydrochloride), Adrucil
(Fluorouracil), Afatinib Dimaleate, Afinitor (Everolimus), Aldara
(Imiquimod), Aldesleukin, Alemtuzumab, Alimta (Pemetrexed
Disodium), Aloxi (Palonosetron Hydrochloride), Ambochlorin
(Chlorambucil), Amboclorin (Chlorambucil), Aminolevulinic Acid,
Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex
(Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic
Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemi,
Avastin (Bevacizumab), Axitinib, Azacitidine, BEACOPP, Bendamustine
Hydrochloride, BEP, Bevacizumab, Bexarotene, Bexxar (Tositumomab
and I 131 Iodine Tositumomab), Bicalutamide, Bleomycin, Bortezomib,
Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin, Busulfan,
Busulfex (Busulfan), Cabazitaxel, Cabozantinib-S-Malate, CAF,
Campath (Alemtuzumab), Camptosar (Irinotecan Hydrochloride),
Capecitabine, CAPDX, Carboplatin, Carboplatin-Taxol, Carfilzomib,
Casodex (Bicalutamide), CeeNU (Lomustine), Cerubidine (Daunorubicin
Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine),
Cetuximab, Chlorambucil, Chlorambucil-Prednisone, CHOP, Cisplatin,
Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine),
Clolar (Clofarabine), CMF, Cometriq (Cabozantinib-S-Malate), COPP,
COPP-ABV, Cosmegen (Dactinomycin), Crizotinib, CVP,
Cyclophosphamide, Cyfos (Ifosfamide), Cytarabine, Cytarabine,
Liposomal, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide),
Dabrafenib, Dacarbazine, Dacogen (Decitabine), Dactinomycin,
Dasatinib, Daunorubicin Hydrochloride, Decitabine, Degarelix,
Denileukin Diftitox, Denosumab, DepoCyt (Liposomal Cytarabine),
DepoFoam (Liposomal Cytarabine), Dexrazoxane Hydrochloride,
Docetaxel, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin
Hydrochloride, Doxorubicin Hydrochloride Liposome, Dox-SL
(Doxorubicin Hydrochloride Liposome), DTIC-Dome (Dacarbazine),
Efudex (Fluorouracil), Elitek (Rasburicase), Ellence (Epirubicin
Hydrochloride), Eloxatin (Oxaliplatin), Eltrombopag Olamine, Emend
(Aprepitant), Enzalutamide, Epirubicin Hydrochloride, EPOCH,
Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib),
Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia
chrysanthemi), Etopophos (Etoposide Phosphate), Etoposide,
Etoposide Phosphate, Evacet (Doxorubicin Hydrochloride Liposome),
Everolimus, Evista (Raloxifene Hydrochloride), Exemestane, Fareston
(Toremifene), Faslodex (Fulvestrant), FEC, Femara (Letrozole),
Filgrastim, Fludara (Fludarabine Phosphate), Fludarabine Phosphate,
Fluoroplex (Fluorouracil), Fluorouracil, Folex (Methotrexate),
Folex PFS (Methotrexate), Folfiri, Folfiri-Bevacizumab,
Folfiri-Cetuximab, Folfirinox, Folfox (Leucovorin, Fluorouracil,
Oxaliplatin), Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil
(Recombinant HPV Quadrivalent Vaccine), Gazyva (Obinutuzumab),
Gefitinib, Gemcitabine Hydrochloride, Gemcitabine-Cisplatin,
Gemcitabine-Oxaliplatin, Gemtuzumab Ozogamicin, Gemzar (Gemcitabine
Hydrochloride), Gilotrif (Afatinib Dimaleate), Gleevec (Imatinib
Mesylate), Glucarpidase, Goserelin Acetate, Halaven (Eribulin
Mesylate), Herceptin (Trastuzumab), HPV Bivalent Vaccine,
Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin
(Topotecan Hydrochloride), Hyper-CVAD, Ibritumomab Tiuxetan,
Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride), Ifex
(Ifosfamide), Ifosf amide, Ifosfamidum (Ifosfamide), Imatinib
Mesylate, Imbruvica (Ibrutinib), Imiquimod, Inlyta (Axitinib),
Intron A (Recombinant Interferon Alfa-2b), Iodine 131 Tositumomab
and Tositumomab, Ipilimumab, Iressa (Gefitinib), Irinotecan
Hydrochloride, Istodax (Romidepsin), Ixabepilone, Ixempra
(Ixabepilone), Jakafi (Ruxolitinib Phosphate), Jevtana
(Cabazitaxel), Kadcyla (Ado-Trastuzumab Emtansine), Keoxifene
(Raloxifene Hydrochloride), Kepivance (Palifermin), Kyprolis
(Carfilzomib), Lapatinib Ditosylate, Lenalidomide, Letrozole,
Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate,
Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox
(Doxorubicin Hydrochloride Liposome), Liposomal Cytarabine,
Lomustine, Lupron (Leuprolide Acetate), Lupron Depot (Leuprolide
Acetate), Lupron Depot-Ped (Leuprolide Acetate), Lupron Depot-3
Month (Leuprolide Acetate), Lupron Depot-4 Month (Leuprolide
Acetate), Marqibo (Vincristine Sulfate Liposome), Matulane
(Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megace
(Megestrol Acetate), Megestrol Acetate, Mekinist (Trametinib),
Mercaptopurine, Mesna, Mesnex (Mesna), Methazolastone
(Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate),
Mexate (Methotrexate), Mexate-AQ (Methotrexate), Mitomycin C,
Mitozytrex (Mitomycin C), MOPP, Mozobil (Plerixafor), Mustargen
(Mechlorethamine Hydrochloride), Mutamycin (Mitomycin C), Myleran
(Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab
Ozogamicin), Nanoparticle Paclitaxel (Paclitaxel Albumin-stabilized
Nanoparticle Formulation), Navelbine (Vinorelbine Tartrate),
Nelarabine, Neosar (Cyclophosphamide), Neupogen (Filgrastim),
Nexavar (Sorafenib Tosylate), Nilotinib, Nolvadex (Tamoxifen
Citrate), Nplate (Romiplostim), Obinutuzumab, Ofatumumab,
Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ontak
(Denileukin Diftitox), OEPA, OPPA, Oxaliplatin, Paclitaxel,
Paclitaxel Albumin-stabilized Nanoparticle Formulation, Palifermin,
Palonosetron Hydrochloride, Pamidronate Disodium, Panitumumab,
Paraplat (Carboplatin), Paraplatin (Carboplatin), Pazopanib
Hydrochloride, Pegaspargase, Peginterferon Alfa-2b, PEG-Intron
(Peginterferon Alfa-2b), Pemetrexed Disodium, Perjeta (Pertuzumab),
Pertuzumab, Platinol (Cisplatin), Platinol-AQ (Cisplatin),
Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib
Hydrochloride, Pralatrexate, Prednisone, Procarbazine
Hydrochloride, Proleukin (Aldesleukin), Prolia (Denosumab),
Promacta (Eltrombopag Olamine), Provenge (Sipuleucel-T), Purinethol
(Mercaptopurine), Radium 223 Dichloride, Raloxifene Hydrochloride,
Rasburicase, R-CHOP, R-CVP, Recombinant HPV Bivalent Vaccine,
Recombinant HPV Quadrivalent Vaccine, Recombinant Interferon
Alfa-2b, Regorafenib, Revlimid (Lenalidomide), Rheumatrex
(Methotrexate), Rituxan (Rituximab), Rituximab, Romidepsin,
Romiplostim, Rubidomycin (Daunorubicin Hydrochloride), Ruxolitinib
Phosphate, Sclerosol Intrapleural Aerosol (Talc), Sipuleucel-T,
Sorafenib Tosylate, Sprycel (Dasatinib), Stanford V, Sterile Talc
Powder (Talc), Steritalc (Talc), Stivarga (Regorafenib), Sunitinib
Malate, Sutent (Sunitinib Malate), Sylatron (Peginterferon
Alfa-2b), Synovir (Thalidomide), Synribo (Omacetaxine
Mepesuccinate), Tafinlar (Dabrafenib), Talc, Tamoxifen Citrate,
Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride),
Targretin (Bexarotene), Tasigna (Nilotinib), Taxol (Paclitaxel),
Taxotere (Docetaxel), Temodar (Temozolomide), Temozolomide,
Temsirolimus, Thalidomide, Thalomid (Thalidomide), Toposar
(Etoposide), Topotecan Hydrochloride, Toremifene, Torisel
(Temsirolimus), Tositumomab and 1 131 Iodine Tositumomab, Totect
(Dexrazoxane Hydrochloride), Trametinib, Trastuzumab, Treanda
(Bendamustine Hydrochloride), Trisenox (Arsenic Trioxide), Tykerb
(Lapatinib Ditosylate), Vandetanib, VAMP, Vectibix (Panitumumab),
VelP, Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar
(Vinblastine Sulfate), Vemurafenib, VePesid (Etoposide), Viadur
(Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine Sulfate,
Vincasar PFS (Vincristine Sulfate), Vincristine Sulfate,
Vincristine Sulfate Liposome, Vinorelbine Tartrate, Vismodegib,
Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib
Hydrochloride), Wellcovorin (Leucovorin Calcium), Xalkori
(Crizotinib), Xeloda (Capecitabine), Xelox, Xgeva (Denosumab),
Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamide), Yervoy
(Ipilimumab), Zaltrap (Ziv-Aflibercept), Zelboraf (Vemurafenib),
Zevalin (Ibritumomab Tiuxetan), Zinecard (Dexrazoxane
Hydrochloride), Ziv-Aflibercept, Zoladex (Goserelin Acetate),
Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid),
and Zytiga (Abiraterone Acetate).
[0328] In certain embodiments, D is a PBD dimer, calicheamicin,
speromycin, tubulysin B, rhizoxin, dolastatin, didemnin B,
camptothecin, CBI, temsirolimus, actinomycin D, epothilone B,
taxol, cryptophycin, SN38, velcade, bruceantin, DAVLBH, DM1,
Phyllanthoside, Alimta, T2 Toxin, MMC, vantalanib, vinorelbine,
brefeldin, sunitinib, daunomycin, semaxanib, tarceva, iressa,
irinotecan, LY-541503, geldanomycin, gemcitabine, methotrexate,
gleevec, topotecan, bleomycin, doxorubicin, cisplatin, N-mustards,
etoposide, or 5-FU.
[0329] In certain embodiments, D is an anthracycline. In certain
embodiments, D is a taxane. In certain embodiments, D is
gemcitabine. In certain embodiments, D is doxorubicin. In certain
embodiments, D is docetaxel. In certain embodiments, D is SN38. In
certain embodiments, D is monomethyl auristatin E. In certain
embodiments, D is dexamethasone. In certain embodiments, D is
celecoxib. In certain embodiments, D is gentamicin.
[0330] In certain embodiments, D is an intracellular permeation
enhancing agent. For example, D may be a functionalized ketoacid,
6-oxo-6-phenylhexanoic acid, 8-oxo-8-phenyloctanoic acid,
8-(2,5-dichlorophenyl)-8-oxooctanoic acid, a functionalized
ketoester or aldehyde, a modified amino acid, modified amino acids,
N-[8-(2-hydroxybenzoyl)aminooctanoic acid,
N-[8-(2-hydroxybenzoyl)aminodecanoic acid,
N-(5-chlorosalicyloyl)-8-aminocaprylic acid,
N-[4-(4-chloro-2-hydroxybenzoyl)amino 1 butanoic acid, 2-ethylhexyl
2-hydroxybenzoate, 5-cyclohexyl-5-oxovaleric acid,
6-cyclohexyl-6-oxohexanoic acid, 7-cyclohexyl-7-oxoheptanoic acid,
8-cyclohexyl-8-oxooctanoic acid, 4-cyclopentyl-4-oxobutyric acid,
5-cyclopentyl-5-oxovaleric acid, 6-cyclopentyl-6-oxohexanoic acid,
7-cyclopentyl-7-oxoheptanoic acid, 8-cyclopentyl-8-oxooctanoic
acid, 4-cyclobutyl-4-oxobutyric acid, 5-cyclobutyl-5-oxovaleric
acid, 6-cyclobutyl-6-oxohexanoic acid, 7-cyclobutyl-7-oxoheptanoic
acid, 8-cyclobutyl-8-oxooctanoic acid, 4-cyclopropyl-4-oxobutyric
acid, 5-cyclopropyl-5-oxovaleric acid, 6-cyclopropyl-6-oxohexanoic
acid, 7-cyclopropyl-7-oxoheptanoic acid,
8-cyclopropyl-8-oxooctanoic acid,
8[(3-methylcyclohexyl)oxyloctanoic acid,
7-[(3-methylcyclohexyl)oxylheptanoic acid,
6-[(3-methylcyclohexyl)oxylhexanoic acid,
5-[(3-methylcyclohexyl)oxylpentanoic acid,
4-[(3-methylcyclohexyl)oxylbutanoic acid,
3-[(3-methylcyclohexyl)oxylpropanoic acid, octisalate, a
diketopiperazines, saponin, an acylcarnitine, an alkanoylcholine, a
taurodihydrofusidate, a sulphoxide, an oxazolidinone, a
pyrrolidone, an alcohol or alkanol, a benzoic acid, a glycol, a
surfactant, a terpene, a functionally effective salt of any of the
foregoing, a derivative of any of the foregoing, or combinations
thereof
3. Compounds
[0331] In certain embodiments, the disclosure provides for
intermediate compounds that are useful in the processes described
herein. Thus, in one embodiment, provided is a compound selected
from Table 1, or a salt thereof. In another embodiment, provided is
an enantiomerically enriched composition comprising a compound
selected from Table 1, or a salt thereof.
[0332] In Table 1, and as used throughout, it can be appreciated
that the straight bolded or dashed bond is used to indicate
relative stereochemistry, and the wedged bolded or dashed bond is
used to indicate absolute stereochemistry. Where the composition is
identified as enantiomerically enriched, it is intended that the
composition comprises more than 50% of a single enantiomer, or at
least about 55%, or at least about 60%, or at least about 65%, or
at least about 70%, or at least about 75%, or at least about 80%,
or at least about 85%, or at least about 90%, or at least about
95%, or at least about 97%, or about 99% ee.
TABLE-US-00001 TABLE 1 Formula Structure IVC ##STR00073## IVD
##STR00074## IVE ##STR00075## VC-1 ##STR00076## VD-1 ##STR00077##
VE-1 ##STR00078## VIC ##STR00079## VID ##STR00080## VIE
##STR00081## VIIC ##STR00082## VIID ##STR00083## VIIE ##STR00084##
VIIIC ##STR00085## VIIID ##STR00086## VIIIE ##STR00087## IXC
##STR00088## IXD ##STR00089## IXE ##STR00090## XC ##STR00091## XD
##STR00092## XE ##STR00093##
[0333] It is appreciated that certain features described herein,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features described herein, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination.
All combinations of the embodiments pertaining to the chemical
groups represented by the variables contained within Formula I, are
specifically embraced by herein just as if each and every
combination was individually and explicitly recited, to the extent
that such combinations embrace compounds that result in stable
compounds (i.e., compounds that can be isolated, characterized and
tested for biological activity).
EXAMPLES
[0334] The compounds of the disclosure may be prepared using
methods disclosed herein and routine modifications thereof which
will be apparent given the disclosure herein and methods well known
in the art. Conventional and well-known synthetic methods may be
used in addition to the teachings herein. The synthesis of
compounds described herein, may be accomplished as described in the
following examples. If available, reagents may be purchased
commercially, e.g. from Sigma Aldrich or other chemical suppliers.
Unless otherwise noted, the starting materials for the following
reactions may be obtained from commercial sources.
Example 1: Chiral Resolution of
(Z)-1-Methylcyclooct-4-ene-1-carboxylic acid
[0335] The following procedure produces a single enantiomer of
compound IV in .gtoreq.97% ee on the kilogram-scale from racemic
starting material, whereas previous reports form compound IV only
on small scale as the racemate (Rossin, R. et al. Bioconjugate
Chem. 2016, 1697-1706).
##STR00094##
[0336] (Z)-1-methylcyclooct-4-ene-1-carboxylic acid (34.3 kg) was
dissolved in EA (1355 kg). A solution of cinchonidine (60 kg) in
DCM (460 kg) was charged at 35-40.degree. C. The mixture was
stirred for 4 h at 45.degree. C., and then cooled down to
12.degree. C. for another 8 hrs. The resulting suspension was
filtered. The collected cake need to be further purified by
recrystallization.
[0337] 1.sup.st recrystallization: The salt (220 g) was dissolved
completely in isopropanol (1 L) and acetone (5 L) at 60.degree. C.
The mixture was kept at 10-15.degree. C. overnight. Filtered and
dried to give 148 g product, 28.0% ee.
[0338] 2.sup.nd recrystallization: The salt (148 g) was dissolved
completely in Isopropanol (750 mL) and Acetone (3850 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 85.2 g product, 54.0% ee. The mother
liquor was concentrated to give 62.8 g solid.
[0339] 3.sup.rd recrystallization: The salt (85.2 g) was dissolved
completely in Isopropanol (420 mL) and Acetone (2100 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 66.0 g product, 74.3% ee. The mother
liquor was concentrated to give 19.0 g solid.
[0340] 4.sup.th recrystallization: The salt (66.0 g) was dissolved
completely in Isopropanol (330 mL) and Acetone (1650 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 42.7 g product, 83.4% ee. The mother
liquor was concentrated to give 13.3 g solid.
[0341] 5.sup.th recrystallization: The salt (42.7 g) was dissolved
completely in Isopropanol (210 mL) and Acetone (1050 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 31.8 g product, 91.0% ee. The mother
liquor was concentrated to give 10.9 g solid.
[0342] 6.sup.th recrystallization: The salt (31.8 g) was dissolved
completely in Isopropanol (160 mL) and Acetone (800 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 26.2 g product, 95.3% ee. The mother
liquor was concentrated to give 5.6 g solid.
[0343] The concentrates of the mother liquors (ee >0%) can be
combined and purified by several rounds of recrystallization to
give more single isomer of 4.
[0344] The solid of the salt (single isomer of
(Z)-1-methylcyclooct-4-ene-1-carboxylic acid with cinchonidine, 6
kg) was mixed with water (35.0 kg). The mixture was added HCl
solution (2.0 kg of 12N conc. HCl diluted with 10.0 kg water) at
20-30.degree. C. to adjust pH to 1. The resulting mixture was
washed with Hexane (3.times.15.0 kg). The combined organic phases
were washed with brine (10 kg). The organic phase was concentrated
at 35-55.degree. C. to give a single isomer of the title compound
as an oil.
[0345] Chromatography Conditions:
TABLE-US-00002 Column Superchiral S-AD Column size 0.46 cm I.D.
.times. 15 cm L, 5 um Injection 5 .mu.L Mobile phase
Hexane/EtOH/DEA = 99/1/0.03 (v/v/v) Flow rate 1.0 mL/min Wavelength
UV 210 nm and Advances Laser Polarimeter Temperature 15.degree.
C.
% ee Upgrade Following Salt Break:
[0346] Salt of converted to free acid of
(Z)-1-methylcyclooct-4-ene-1-carboxylic acid by addition of HCl
[0347] Dissolve (Z)-1-methylcyclooct-4-ene-1-carboxylic acid and
add desired enantiomer seed to induce crystallization [0348]
Precipitation is observed, though analysis indicates there is no
difference in % ee between the solid and supernatant [0349]
Suggestive that racemate may exist as solid solution, making
enrichment of acid form unfeasible
Increasing Starting Material Purity:
[0349] [0350] Racemate with low purity of 47% was spiked into pure
enriched (Z)-1-methylcyclooct-4-ene-1-carboxylic acid (33% ee)
[0351] Spiking of impurity did not impact the relative solubility
of desired and undesired enantiomers [0352] Accordingly, no
significant % ee improvement was observed using pure
(Z)-1-methylcyclooct-4-ene-1-carboxylic acid compared to impure
(Z)-1-methylcyclooct-4-ene-1-carboxylic acid for the resolution
process
Dependence of Relative Solubility of Desired/Undesired Enantiomers
on % ee:
[0352] [0353] The solubility of desired and undesired enantiomers
was measured in samples of various degrees of enantioenrichment,
ranging from 0-88% ee [0354] For racemic material, solubility of
the undesired enantiomer exceeds that of desired enantiomer [0355]
However, once 46% ee is reached, the solubility trend reverses,
with the solubility of the desired enantiomer salt exceeding that
of the undesired enantiomer salt [0356] This switch complicates the
development of a high yielding chiral resolution process to reach
.gtoreq.97% ee starting from racemate
[0357] The other solvents were screened and results shown
below.
TABLE-US-00003 Supernatant Final solid Starting solid volume ee
Step Weigh (g) ee Solvent (mL) ee Yield yield salt formation 0.83
0.0% Acetone/H.sub.2O 33.6 49.3% 50.1% 0.25 1.sup.st
recrystallization 0.506 53.70% (19:1) 11.7 87.5% 44.6% 0.39
2.sup.nd recrystallization 42.7 83.4% IPA/Acetone 1:5 1260 91.0%
74.5% 0.68 3.sup.rd recrystallization 31.8 91.0% 960 95.3% 82.4%
0.79 Final Purity: 81.2% Overall Yield: 13.7%
Example 2: Large Scale Synthesis of Enantioenriched
cis-(Z)-6-Hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid
[0358] Process for the production of single enantiomer (.gtoreq.97%
ee) cis-(Z)-6-hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid on
the kilogram-scale from racemic starting material. Literature
reports synthesis of 17.5 g racemic
cis-(Z)-6-hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid.
(Rossin, R. et al. Bioconjugate Chem. 2016, 1697-1706).
##STR00095##
[0359] Compound 4 (34.3 kg) was dissolved in EA (1355 kg). A
solution of cinchonidine (60 kg) in DCM (460 kg) was charged at
35-40.degree. C. The mixture was stirred for 4 h at 45.degree. C.,
and then cooled down to 12.degree. C. for another 8 hrs. The
resulting suspension was filtered. The collected cake need to be
further purified by recrystallization.
[0360] 1.sup.st recrystallization: The salt (220 g) was dissolved
completely in isopropanol (1 L) and Acetone (5 L) at 60.degree. C.
The mixture was kept at 10-15.degree. C. overnight. Filtered and
dried to give 148 g product, 28.0% ee.
[0361] 2.sup.nd recrystallization: The salt (148 g) was dissolved
completely in isopropanol (750 ml) and Acetone (3850 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 85.2 g product, 54.0% ee. The mother
liquor was concentrated to give 62.8 g solid.
[0362] 3.sup.rd recrystallization: The salt (85.2 g) was dissolved
completely in isopropanol (420 ml) and Acetone (2100 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 66.0 g product, 74.3% ee. The mother
liquor was concentrated to give 19.0 g solid.
[0363] 4.sup.th recrystallization: The salt (66.0 g) was dissolved
completely in isopropanol (330 ml) and Acetone (1650 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 42.7 g product, 83.4% ee. The mother
liquor was concentrated to give 13.3 g solid.
[0364] 5.sup.th recrystallization: The salt (42.7 g) was dissolved
completely in Isopropanol (210 mL) and Acetone (1050 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 31.8 g product, 91.0% ee. The mother
liquor was concentrated to give 10.9 g solid.
[0365] 6.sup.th recrystallization: The salt (31.8 g) was dissolved
completely in Isopropanol (160 mL) and Acetone (800 mL) at
60.degree. C. The mixture was kept at 10-15.degree. C. overnight.
Filtered and dried to give 26.2 g product, 95.3% ee. The mother
liquor was concentrated to give 5.6 g solid.
[0366] The concentrates of the mother liquors (ee >0%) can be
combined and purified by several rounds of recrystallization to
give more single isomer of (Z)-1-methylcyclooct-4-ene-1-carboxylic
acid.
[0367] The solid of the salt (single isomer of
(Z)-1-methylcyclooct-4-ene-1-carboxylic acid with cinchonidine, 6
kg) was mixed with water (35.0 kg). The mixture was added HCl
solution (2.0 kg of 12N conc. HCl diluted with 10.0 kg water) at
20-30.degree. C. to adjust pH to 1. The resulting mixture was
washed with Hexane (3.times.15.0 kg). The combined organic phases
were washed with brine (10 kg). The organic phase was concentrated
at 35-55.degree. C. to give single isomer of
(Z)-1-methylcyclooct-4-ene-1-carboxylic acid as an oil.
[0368] The product (2.8 kg) was taken in mixture of DCM (22.2 kg)
and water (16.7 kg) and NaHCO.sub.3 (4.8 kg) was added. The
reaction mixture was cooled to 0-5.degree. C. and added mixture of
KI (8.2 kg) and iodine (8.4 kg) in portions. The reaction was
stirred at room temperature for 2 h and then sampled for GC. When
the starting material is no more than 2.0a % by GC, the reaction
mixture was quenched slowly with sodium bisulfite (3.4 kg of sodium
bisulfite in 16.7 kg of water) until clear solution appeared. Both
the layers were separated and the aqueous layer was extracted with
DCM (22.2 kg). The combined organic layer was washed with water
(8.4 kg), dried with Na.sub.2SO.sub.4 (1.7 kg) and rotary
evaporation yielded enantiomerically enriched
5-iodo-1-methyl-7-oxabicyclo[4.2.2]decan-8-one (quantitative) which
was used in the next step without further purification.
[0369] The resulting product (4.8 kg) was dissolved in toluene
(21.3 kg) and then DBU (2.9 kg) was added. The mixture was allowed
to stand for 12 hrs at 25-30.degree. C., after which it was heated
under reflux for 4 hrs, at which point GC indicated full conversion
(5-iodo-1-methyl-7-oxabicyclo[4.2.2]decan-8-one <3 a %). After
cooling, the reaction mixture was washed with water (6.4 kg). The
aqueous phases were extracted with toluene (10.7 kg). The organic
phases was dried by Na.sub.2SO.sub.4 (2.9 kg) and then concentrated
to a colorless oil (94% yield).
[0370] (Z)-1-methyl-7-oxabicyclo[4.2.2]dec-4-en-8-one (2.66 kg) was
mixed with methanol (12.8 kg), KHCO.sub.3 (16.0 kg) and water (0.03
kg). The mixture was hold at 28.degree. C. for 24 hrs and monitored
by HPLC. The reaction was deemed complete when the starting
material NMT 26.0%. Filtered, and the cake was washed with
methanol. The filtrate was concentrated at 35-55.degree. C., and
then EA (20 kg) and water (12.58 kg) was added. pH value of the
mixture was adjusted to 2-3 by 2N HCl solution. Let the layers
separated, and the aqueous phase was washed with EA (4.times.8.0
kg). The combined organic phases were washed with brine (17.2 kg),
dried by Na2SO4 (1.3 kg) and then concentrated at 35-55.degree. C.
The residue was purified by chromatography using hexane and EA
(50:1) as the eluent, affording the pure title product as a
colorless oil. (Note: The starting material can be recycled and the
mixed fractions also can be purified again to provide more
products.)
Example 3: Synthesis of Enantioenriched 2,5-Dioxopyrrolidin-1-yl
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-
-4-ene-1-carboxylate from
cis-(E)-6-Hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid
[0371] Process for the robust synthesis of high purity
2,5-dioxopyrrolidin-1-yl
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-
-4-ene-1-carboxylate from TCO starting material
cis-(E)-6-Hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid in 75%
yield on the 100 gram-scale without the use of chromatography.
Literature reference reports synthesis of 400 mg
2,5-dioxopyrrolidin-1-yl
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-
-4-ene-1-carboxylate in 46% yield, requiring purification by silica
gel chromatography (Rossin, R. et al. Bioconjugate Chem. 2016,
1697-1706).
##STR00096##
[0372] A mixture of
cis-(E)-6-Hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid (1
equiv.), N,N'-Disuccinimidyl carbonate (DSC) (4.3 equiv.), DIPEA
(7.4 equiv.) in dry acetonitrile (20 volumes) is stirred at 22 to
25.degree. C. until the intermediate 2,5-dioxopyrrolidin-1-yl
cis-(E)-6-hydroxy-1-methylcyclooct-4-ene-1-carboxylate is less than
0.5% AUC by UPLC (7-9 h). The resulting suspension is added to DI
water (50 volumes) at room temperature and the resulting mixture is
stirred for about 15 min. The resulting solid suspension is
filtered, washed with DI water (3.times.2 volumes), and dried on
the filter under vacuum for approximately 1 h.
[0373] The solid crude 2,5-dioxopyrrolidin-1-yl
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-
-4-ene-1-carboxylate is suspended in acetonitrile (.about.2
volumes) and mixed at 35 to 45.degree. C. for approximately 1 h.
The mixture is cooled to approximately 15.degree. C. and filtered.
The cake is washed with acetonitrile (2.times.1 volumes), and dried
under vacuum on the filter for .about.60 min to give
enantiomerically enriched 2,5-dioxopyrrolidin-1-yl
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-
-4-ene-1-carboxylate as a white to off white crystalline solid in
.about.99% AUC purity by UPLC at 214 nm in about 74-80% isolated
yield.
[0374] From 61.8 g of
cis-(E)-6-Hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid, 106.0 g
of 2,5-dioxopyrrolidin-1-yl
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-
-4-ene-1-carboxylate was obtained in 98.6% AUC purity with 75.4%
isolated yield.
[0375] Analytical Method:
TABLE-US-00004 Column Supelco Ascentis Express C18 (150 .times. 3.0
mm, 2.7 .mu.m), Cat No. 53816-U Gradient Timetable Time (min) A%
(H.sub.2O/0.1% TFA) B% (ACN/0.1% TFA) Flow (mL/min) 0.00 98.00 2.00
0.600 12.00 5.00 95.00 0.600 14.00 5.00 95.00 0.600 14.10 98.00
2.00 0.600 16.00 98.00 2.00 0.600 Wavelength 214,254 nm Compound,
Compound Name Retention time (min) RRT retention 15 5.48 0.64 time,
relative retention time ##STR00097## 5.5 0.65
cis-(E)-6-Hydroxy-1-methylcyclooct-4- ene-1-carboxylic acid
##STR00098## 5.87 0.69 (structure not confirmed)
cis-(E)-6-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-
1-methylcyclooct-4-ene-1-carboxylic acid ##STR00099## 7.07 0.83
2,5-dioxopyrrolidin-l-yl cis-(E)-6-hydroxy-1-
methylcyclooct-4-ene-1-carboxylate ##STR00100## 8.52 1.00
2,5-dioxopyrrolidin-1-yl cis-(E)-6-((((2,5-
dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-
1-methylcyclooct-4-ene-1-carboxylate
Example 4: Chiral Resolution of Compound VIIC
##STR00101##
[0377] Resolution screening on compound VIIC was performed using
each of the chiral bases (S)-2-amino-1-propanol (L-alaninol),
(R)-(+)-1-phenylethylamine, L-(-)-2-amino-1-butanol,
(1R,2S)-(-)-ephedrine, (S)-(+)-2-amino-3-methyl-1-butanol
(L-valinol), (S)-(-)-N-benzyl-alpha-methylbenzylamine,
(+)-dehydroabietylamine,
(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,
(R)-(+)-3-pyrrolidinol, (S)-(+)-2-pyrrolidinemethanol (L-prolinol),
(S)-(-)-1-(1-naphthyl)ethylamine, (R)-1-amino-2-propanol, L-proline
amide, (1R,2R)-(-)-pseudoephedrine, L-phenylalaninol,
(1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol, cinchonine,
quinidine, quinine, cinchonidine, (S)-(+)-L-phenylglycinol,
(R)-(-)-2-phenylglycine amide, (R)-(+)-2-phenylpropylamine,
L-phenylalanine amide, (S)-diphenyl-2-pyrrolidine methanol,
(1S,2S)-(+)-N-p-tosyl-1,2-diphenylethylenediamine,
(1S,2R)-(+)-2-amino-1,2 diphenyl-ethanol, N-methyl-D-glucamine,
(1S,2S)-(-)1,2-diphenylethylene diamine,
(1R,2R)-diaminocyclohexane, (R)-(2-methoxyphenyl)ethylamine,
(S)-p-chlorophenylethylamine, (R)-(+)-1-(4-methylphenyl)ethylamine,
(S)-2-amino-1,1-diphenyl-1-propanol,
(1S,2S)-(-)1,2-diphenylethylene diamine, and
(1R,2R)-diaminocyclohexane, in each of the following solvents:
water, acetonitrile, 1:1 water:ethanol, ethanol, IPA, MEK, iPrOAc,
and dioxane. Select results of the resolution of compound VIIC on
100 mg scale, starting in 18 mL solvent are shown below.
TABLE-US-00005 Toluene EtOAc iPrOAc TBME Et.sub.2O acetone MEK
R-1-Amino-2-propanol 1 eq .times. -2/48 -7/37 -8/52 -3/54 -62/65
-7/48 0.5 eq -48/58 .times. 0.5 eq. + 0.5 eq NaOH .times. 0.5 eq. +
0.5 eq NaOH .times. R-Phenylglycinol 1 eq x x 56/-75 x x x x 0.5
eq. 61/-42
[0378] 1. 100 mg Compound VIIC and 44 mg R-aminopropanol in 18 mL
iPrOAc: S=109 mg-7% ML=36 mg 37%. [0379] 2. 100 mg Compound VIIC
and 22 mg R-aminopropanol in 18 mL iPrOAc: S=68 mg-48% ML=54 mg
58%. [0380] 3. 100 mg Compound VIIC and 81 mg R-phenylglycinol in
18 mL iPrOAc: S=79 mg 56% ML=98 mg-75%. [0381] 4. 100 mg Compound
VIIC and 40 mg R-phenylglycinol in 18 mL iPrOAc: S=58 mg 61% ML=86
mg-42%. [0382] 5. 100 mg Compound VIIC and 150 mg
L-diphenylpyrolidine methanol in 18 mL iPrOAc: S=167 mg 0% ML=50 mg
0%. [0383] 6. 100 mg Compound VIIC and 75 mg L-diphenylpyrolidine
methanol in 18 mL iPrOAc: S=104 mg 0% ML=63 mg 0%.
Example 5: Chiral Resolution of
(Z)-6-hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid
[0384] The following example shows the chiral resolution of
(Z)-6-hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid using
(R)-2-amino-2-phenylethan-1-ol, which provides the opposite
enantiomer of that provided by Example 2. The (-) sign is assigned
to the % ee in order to distinguish between both of the
enantiomers, and does not represent optical rotation.
[0385] (Z)-6-hydroxy-1-methylcyclooct-4-ene-1-carboxylic acid (8.00
g, 1 eq, 43.4 mmol) was dissolved in 900 isopropyl acetate at
68.degree. C. in a 2 L three necked flask (some minor white
insoluble material smeared onto the glass and remained there during
the entire first step). (R)-2-amino-2-phenylethan-1-ol (5.96 g, 1
eq, 43.4 mmol) was added and the mixture was stirred with and
overhead stirrer at 135 rpm.
[0386] The clear mixture was cooled at 10.degree. C./hour and
seeded upon every two degrees cooling, using seeding crystals with
-61% ee. At 48.degree. C. crystallization occurred. The mixture was
further cooled to 35.degree. C. at 10.degree. C./hour and
subsequently allowed to reach room temperature overnight.
[0387] Filtration gave 7.2 gram of solids with ee=-55% and 6.6 gram
of material in the mother liquor with ee=83%.
[0388] 6.2 gram of the solids obtained in step 1 were suspended in
255 mL isopropylacetate in a 1 L three necked flask and heated to
70.degree. C. while stirring with an overhead stirrer at 135 rpm.
After 5 minutes, the mixture was allowed to reach room temperature
overnight. Filtration gave 5.1 gram of solids with ee=-76% and 1.0
gram of material in the mother liquor with ee=72%.
[0389] 3.7 gram of the solids obtained in step 2 were suspended in
20 mL 2-butanone in a 100 mL round bottomed flask and heated to
reflux while stirring with a magnetic stirrer. 12 mL methanol was
added, after which the suspension became a clear solution. The
mixture was allowed to reach room temperature overnight, during
which it had crystallized. Filtration gave 2.0 gram of solids with
ee=-92% and 1.7 gram of material in the mother liquor with
ee=-71%.
[0390] 1.0 gram of the solids obtained in step 3 were suspended in
10 mL isopropanol in a 100 mL round bottomed flask and heated to
60.degree. C. while stirring with a magnetic stirrer. After 5
minutes, the mixture was allowed to reach room temperature
overnight. Filtration gave 0.85 gram of solids with ee=-100% and
0.15 gram of material in the mother liquor with ee=-56%.
Example 6: Synthesis of trans-Cyclooctene (TCO)-doxorubicin
Conjugate 12
[0391] Procedures to Compound 11:
[0392] Process for the synthesis of trans-cyclooctene
(TCO)-doxorubicin conjugate 11 from TCO starting material 10 in 98%
yield on the single gram-scale. Literature reference reports
synthesis of 134 mg 11 in 68% yield. (Rossin, R. et al.
Bioconjugate Chem. 2016, 1697-1706).
##STR00102##
[0393] To a DMF (10 mL, 10 V) solution of Doxorubicin HCl (1.0 g,
1.72 mmol, 1.0 eq.) was added 10 (874.0 mg, 1.2 eq.) followed by
adding DIPEA (0.9 mL, 3.0 eq.). The mixture was stirred at RT for
1.5 h, HPLC showed the formation of the product 11 (LCAP: 88.5%)
and a small amount of Doxorubicin (LCAP: 0.3%). Assay yield of 11
was 102.6%. The reaction mixture was diluted with DCM (40 mL) and
washed with water (total: 250 mL, HPLC monitored to make sure most
DMF was washed out) and brine (10 mL). The DCM extracts were dried
over Na.sub.2SO.sub.4 and concentrated to give crude residue.
Isolated 1.7 g crude 11 (95.1% LCAP).
[0394] The residue was purified by silica gel chromatography to
give 11 as a red solid. Isolated 1.44 g purified 11 (94.8% LCAP and
97.1% LCWP) in a 98.0% uncorrected yield. Neither 10 nor
Doxorubicin were detected in the isolated material.
[0395] As the purity of 11 did not seem to improve significantly
after silica gel purification, this step may not be necessary.
[0396] Procedures to Compound 12:
##STR00103##
[0397] One-pot method for 10 to 12, 89% purity without
chromatography: To a DMF (10 mL, 10 V) solution of Doxorubicin HCl
(1.0 g, 1.72 mmol, 1.0 eq.) was added compound 10 (874.0 mg, 1.2
eq.), followed by adding DIPEA (0.9 mL, 3.0 eq.). The mixture was
stirred at RT for 1.25 h, HPLC showed the formation of the product
11 (LCAP: 87.3%) and a small amount of Doxorubicin (LCAP: 0.4%).
Assay yield is 95.2%. To the reaction mixture was added a
suspension of glycine (1.29 g, 10.0 eq.),
N,O-bis(trimethylsilyl)acetamide (BSA) (2.11 mL, 5.0 eq.), DIPEA
(6.0 mL, 20.0 eq.) in DCM (20 mL). The resulting mixture was
stirred at RT for 24 h. HPLC showed 87.7% LCAP for 12, 4.4% for
11.
[0398] The reaction mixture was filtered through a pad of Celite,
washed with DCM (3 mL). The filtrate was concentrated to give a
residue (4.9 g), which was mixed with water (26 mL) and added 4 mL
1 N NaOH to help dissolve the solid at 0.degree. C. The mixture was
then extracted with MTBE, but found emulsion was formed, more water
(5 mL) and 1N NaOH (2 mL) and MTBE were added, eventually, two
layers were formed, the aqueous layer (total volume: .about.120 mL)
was extracted with MTBE (3.times.60 mL) and then acidified with 1N
HCl to pH=1-2.
[0399] The orange precipitate was collected by filtration and
washed with water and dried under vacuum to give 1.25 g 12 (89.3%
LCAP) in 89.2% uncorrected yield.
[0400] One-pot method for 10 to 12 with chromatography To a DMF
(2.5 mL, 10 V) solution of Doxorubicin HCl (250 mg, 0.431 mmol, 1.0
eq.) was added compound 10 (218.5 mg, 1.2 eq.), followed by adding
DIPEA (0.23 mL, 3.0 eq.). The mixture was stirred at RT for 3 h,
HPLC showed the formation of the product 11 (LCAP: 91.8%) and a
small amount Doxorubicin (LCAP: 0.3%). Assay yield is 92%. To the
reaction mixture was added a preformed suspension of glycine (323.6
mg, 10 eq.), BSA (0.528 mL, 5 eq.) and DIPEA (1.5 mL, 20 eq.) in 5
mL DCM, which was stirred at RT for 2-3 h. The resulting mixture
was stirred at RT for 25 h. After filtration and concentration, the
residue was subjected to reverse phase ISCO. The collected
fractions were lyophilized.
[0401] One-pot method for 10 to 12, alternative method--reverse
order of addition: To a DMF (2.5 mL, 10 V) solution of Doxorubicin
HCl (250 mg, 0.431 mmol, 1.0 eq.) was added compound 10 (218.5 mg,
1.2 eq.), followed by adding DIPEA (0.23 mL, 3.0 eq.). The mixture
was stirred at RT for 1 h, HPLC showed the formation of the product
11 (LCAP: 88.8%) and a small amount Doxorubicin (LCAP: 0.5%). Assay
yield is 93.3%. This reaction mixture was used directly as
described below.
[0402] i) To a suspension of glycine (64.7 mg, 0.86 mmol, 10 eq.)
in 1 mL DCM were added BSA (0.105 mL, 5 eq.) and DIPEA (0.30 mL, 20
eq.) at RT under nitrogen. The mixture was refluxed for 2 h, then
cooled down to room temperature. To this was added reaction mixture
for 11 (0.5 mL). The resulting mixture was heated at 40.degree. C.
for 5 h and monitored by HPLC. The reaction mixture was then cooled
down to RT, filtered through a pad of Celite, washed with DCM. The
filtrate was concentrated to give a residue (0.64 g), which was
mixed with 0.2 N NaOH (0.5 mL) and the mixture was extracted with
MTBE (2.times.1 mL). The aqueous layer was then acidified with 1 N
HCl (0.2 mL) to pH=4-5. Gum-like precipitates were formed and
collected, which showed 88.7% LCAP for 12. The aqueous is mainly a
mixture of water with DMF.
[0403] ii) To a suspension of glycine (64.7 mg, 0.862 mmol, 10 eq.)
in 1 mL DCM were added BSA (0.105 mL, 10 eq.) and DIPEA (0.30 mL,
40 eq.) at RT under nitrogen. The mixture was stirred at RT for 5
min, then reaction mixture [24-R174] (0.5 mL) was added. The
resulting mixture was stirred at RT for 22 h. HPLC showed 90.4%
LCAP for 12, no other peak is >5% LCAP. The reaction mixture was
filtered through a pad of Celite, washed with DCM. The filtrate was
concentrated to give a residue, which was subjected to reverse
phase ISCO purification. The collected fractions were
lyophilized.
[0404] Comparative Synthesis: Conversion of 11 to 12 using TMSCl as
protection reagent: To a suspension of glycine (89.3 mg, 1.19 mmol,
10 eq.) in 6 mL 60% CHCl.sub.3/MeCN was added TMSCl (127.7 mg, 10
eq.) at RT under nitrogen. The mixture was refluxed for 2 h, then
cooled down to room temperature. DIPEA (0.41 mL, 20 eq.) was added
and followed by compound 11 (100.0 mg, 1.0 eq.). The resulting
mixture was heated at 65.degree. C. for 4.5 h and monitored by
HPLC. The reaction was then diluted with water (10 mL) and
extracted with DCM (3.times.25 mL). The DCM extracts were purified
by silica gel chromatography to give compound 12 (7.3 mg, 24-165-2,
LCAP for 12: 78.8%). The aqueous layer was purified by reverse
phase ISCO (0-50% MeCN/water) to give 12 (19.6 mg, LCAP for 12:
87.6%). Isolated (uncorrected) yield was 28.3%.
[0405] Compound-12-Na Formation:
[0406] A 2000 mL flask was equipped with overhead stirrer,
temperature probe, and nitrogen inlet/outlet. Acetone (5 vol., 128
mL) was charged to the flask and agitated at 20 to 25.degree. C.
under nitrogen. The crude compound 12 (25.6 g, 0.0315 moles, 1
equiv., the amount was from wt. assay %) was slurred with a part of
acetone (7 volumes, 179 mL) and charged to flask. The rest of the
acetone was used to rinse the compound 12 free acid flask and
charged to the 2000 mL flask. The mixture was purged briefly with
nitrogen and then blanket under nitrogen.
[0407] To the stirring suspension, water (3.3 vol. 84.5 mL,
degassed under vacuum to remove oxygen) was added in portions at 20
to 25.degree. C. The mixture was completely dissolved (checked it
with flush light).
[0408] NaHCO.sub.3 (0.592 M, 5% in USP water, 53.3 mL,
approximately 1 equiv., degassed under vacuum) was added in
portions to the mixture under nitrogen at 20-25.degree. C. with
agitation. The mixture was filterable and stirred at 20 to
25.degree. C. for approximately 30 min.
[0409] To the resulting solution in the 2000 mL flask, acetone
(.about.35 vol. 896 mL) was added through in portions over
.about.10 min at 19 to 24.degree. C. to form solid suspension. The
mixture was stirred at 20-24.degree. C. for .about.30 min.
[0410] Agitation was stopped to allow solids set at bottom of the
flask (over .about.1 min). The mixture was filtered. The flask was
rinsed with acetone (3.times.75 mL) and the rinse was used to wash
the solid cake.
[0411] The wet solid was transferred into 500 mL round bottom flask
and dried under vacuum at room temperature (20 to 25.degree. C.)
until a consistent weight was achieved.
Example 7: Synthesis of Trans-Cyclooctene (TCO)-Doxorubicin
Conjugate 12-Ala
##STR00104##
[0413] General Procedure for compound 11: Compound 10 (240 mg,
0.569 mmol, 1.0 eq) was dissolved in dry DMF (6 mL) followed by the
addition of doxorubicin (395 mg, 0.683 mmol, 1.2 eq, HCl salt) and
N,N-diisopropylethylamine (367 mg, 2.85 mmol, 5.0 eq). The solution
was stirred overnight at r.t. under nitrogen and aluminum foil
protection. The reaction mixture was diluted with DCM, washed with
5% aq citric acid, dH.sub.2O, and brine. The organic layer was
dried over Na.sub.2SO.sub.4 filtered and concentrated under reduced
pressure to afford compound 11 (200 mg) as red solid.
[0414] TLC: DCM/methanol/acetic acid (20:1:0.2);
[0415] R.sub.f (Compound 11)=0.35;
[0416] LC-MS: 851.2 [M+H].sup.+;
[0417] General Procedure for 12-Ala: A mixture of L-alanine (52.6
mg, 0.59 mmol, 10 eq), BSA (60 mg, 0.294 mmol, 5.0 eq), DIPEA (152
mg, 1.18 mmol, 20.0 eq) in DCM (0.5 mL) was stirred for 30 min, and
added to a solution of compound 11 (50.0 mg, 0.059 mmol, 1.0 eq) in
DMF (0.2 mL). The reaction mixture was heated at 32.degree. C.
overnight under nitrogen and aluminum foil protection. The reaction
mixture was concentrated to dryness and the residue was diluted
with acetonitrile (2 mL). The resulting crude reaction mixture was
purified by prep-HPLC (5% to 100% CH.sub.3CN in 30 minutes,
neutral, pH 7) to give 12-Ala (2.3 mg) after the fractions with
desired mass were lyophilized to dryness. LC-MS: 846.8 [M+H].sup.+,
822.5 [M-H].sup.-; .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.85
(m, 1H), 7.78 (m, 1H), 7.52 (m, 1H), 5.64 (m, 1H), 5.40 (m, 2H),
5.07 (m, 2H), 4.74 (s, 1H), 4.24 (m, 2H), 3.82 (s, 3H), 3.82 (m,
1H), 3.61 (m, 2H), 2.98 (m, 2H), 2.90 (m, 2H), 2.38-1.74 (m, 10H),
1.33 (d, J=6.3 Hz, 3H), 1.26 (d, J=6.3 Hz, 3H), 1.09 (s, 3H).
Example 8: Comparative Examples
[0418] Evaluation of alternate synthetic approaches to
trans-cyclooctene (TCO)-doxorubicin conjugate (Dox-TCO-Gly).
[0419] Direct Coupling of Glycine to Dox-TCO-NHS (without
Protecting Groups) is Inefficient
##STR00105##
[0420] TMS Protection Route
##STR00106##
[0421] To a suspension of glycine (440 mg, 5.9 mmol, 10 equiv) in
50 mL of CHCl.sub.3:MeCN (60%:40%) was added TMSCl (638 mg, 5.9
mmol, 10 equiv) in one portion. The resulting mixture was stirred
at reflux (80 C) for 2 h and then cooled to room temperature. DIPEA
(2 mL, 12 mmol, 20 equiv) and Dox-TCO-NHS (500 mg, 0.58 mmol) were
added at room temperature and the mixture was then stirred at 65 C
for 6 h. Analysis of crude HPLC indicated 78% yield. After removal
of the solvents, the residue was dissolved in 5 mL water and
purified by reversed phase chromatography (MeCN:water,
0.fwdarw.50%) to afford Dox-TCO-Gly (235 mg, 49%) as an orange
solid.
[0422] Alternate Activating Group: PNP Results in Lower Dox
Coupling Yield Compared to NHS
[0423] PNP--53%
##STR00107##
[0424] NHS--72%
##STR00108##
[0425] Alternate Protecting Group: Fmoc Route--4 Steps, 17%
Overall
##STR00109##
[0426] Alternate Protecting Group: tBu Route--4 Steps, Desired
Product not Obtained
##STR00110##
[0427] Various acidic deprotection conditions screened (e.g. TFA,
AcOH, HCl, H.sub.3PO.sub.2) in different solvents--desired product
never observed. By mass, always observe deprotection along with
addition of water (possibly to Dox glycosidic bond or TCO
alkene).
[0428] Direct Alcohol Monoactivation of TCO--Carboxylic Acid
Activation Favored
##STR00111##
[0429] Alternate Routes to Alcohol Activation--Less Efficient than
NHS Bis-Activation Route
##STR00112## ##STR00113##
Example 9: Pexidartinib-TCO-Glycine Conjugate Via BSA-Protection
Method
[0430] This example provides methods for the conjugation of a TCO
starting material, such as those described herein (e.g., compound
10) to Pexidartinib. Further modification of compound 15 with an
amino acid moiety (e.g., glycine) is contemplated.
##STR00114##
[0431] To a solution of compound 13 (418 mg, 1.0 mmol) in DMF (10
mL) at 0.degree. C. was added NaH (ca. 60%, 44 mg, 1.1 mmol). The
reaction mixture was stirred under N.sub.2 for 1 h before
Bis-NHS-TCO (398 mg, 1.0 mmol) was added. The resulting mixture was
stirred at room temperature for 18 h. The reaction was quenched
with water (10 mL). The product was extracted with ethyl acetate
(2.times.40 mL). The combined organic layers were washed with water
(4.times.15 mL), and brine (15 mL), dried (MgSO.sub.4) and
evaporated in vacuo. The product was purified by flash
chromatography on silica gel eluting with EA/Hex (0%-100%) to give
the intermediate 14 (463 mg, 64%) as a white solid. LCMS:
R.sub.t=1.281, m/z 725 [M+1].sup.+
##STR00115##
[0432] To a solution of N-hydroxylsuccinimide ester 14 (200 mg,
0.28 mmol) and DMF (1.6 mL) were added into a solution of glycine
(207 mg, 2.8 mmol), N,O-bis(trimethylsilyl)acetamide (285 mg, 1.4
mmol) and DIPEA (724 mg, 5.6 mmol) in DCM (3.2 mL). The resulting
mixture was allowed to stir at room temperature for 16 h. The
reaction was monitored by LCMS and HPLC to indicate the majority
(68%) content was the desired product compound 15 (m/z 684.8(+) and
682.5(-), MW: 685.1). The reaction mixture was diluted with DCM (10
mL), and then filtered through a pad of Celite. The filtrate was
concentrated to dryness. The residue was purified by Prep-HPLC
(0.1% formic acid as buffer) to afford compound 15 (116.2 mg, 61%)
as a white solid. LCMS: R.sub.t=1.013, m/z 685 [M+1].sup.+ and 1368
[2M+1].sup.+. .sup.1H NMR (300 MHz, CHCl.sub.3) .delta. 8.61 (s,
1H), 8.46 (d, J=1.8 Hz, 1H), 7.94-7.80 (m, 2H), 7.68-7.60 (m, 2H),
7.57 (s, 1H), 7.50 (dd, J=8.7 and 1.8 Hz, 1H), 6.50 (d, J=9.0 Hz,
1H), 6.34-6.16 (m, 2H), 5.66 (dd, J=16.2 and 2.4 Hz, 1H), 5.57 (s,
1H), 4.59 (s, 2H), 3.92-3.80 (m, 4H), 2.38-1.80 (m, 7H), 1.74-1.68
(m, 1H), 1.17 (s, 3H).
Example 10: Etoposide-TCO Conjugate
[0433] This example provides methods for the conjugation of a TCO
starting material, such as those described herein (e.g., compound
10) to Etoposide.
##STR00116##
[0434] To a solution of etoposide (50 mg, 0.08 mmol) in DMF 5 mL,
TCO-PNP (30 mg, 0.10 mmol) and DMAP (21 mg, 0.16 mmol) were added.
The mixture was stirred for 3 days. and quenched with 20 mL water.
The mixture was extracted with EtOAc (3.times.30 mL) and the
combined organic phase was dried and concentrated. The residue was
purified on column to give etoposide-TCO compound 16 (30 mg, 54%).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 6.84 (s, 1H), 6.53 (s,
1H), 6.27 (s, 2H), 6.03-5.85 (m, 3H), 5.51 (dd, J=16.5, 1.7 Hz,
1H), 5.33 (s, 1H), 4.92 (d, J=3.4 Hz, 1H), 4.74 (q, J=5.0 Hz, 1H),
4.60 (dd, J=15.7, 6.4 Hz, 2H), 4.42 (dd, J=26.1, 16.7 Hz, 1H),
4.29-4.12 (m, 2H), 3.68 (s, 6H), 3.62 (dd, J=17.9, 9.1 Hz, 1H),
3.59-3.52 (m, 1H), 3.41-3.36 (m, 1H), 3.37-3.22 (m, 5H), 2.86 (tdd,
J=10.9, 8.0, 3.3 Hz, 1H), 2.49 (d, J=10.3 Hz, 1H), 2.19 (t, J=11.9
Hz, 1H), 2.08-1.94 (m, 2H), 1.89 (dt, J=15.1, 6.4 Hz, 1H), 1.68
(ddd, J=19.0, 15.3, 9.7 Hz, 2H), 1.59-1.46 (m, 1H), 1.38 (d, J=5.0
Hz, 3H), 1.22-1.10 (m, 1H), 0.81 (td, J=14.6, 5.6 Hz, 1H).
Example 11: Aniline Mustard-TCO Conjugate
##STR00117##
[0436] To a solution of 8-1 (212 mg, 0.72 mmol) in DMF (3 mL) was
added 8-2 (305 mg, 0.72 mmol) and DIEA (279 mg, 2.17 mmol). The
solution was stirred at rt overnight. After removal of solvent, DCM
(30 mL) was added. The organics were washed with saturated
NaHCO.sub.3 (40 mL), water (30 mL), brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated to give a residue. The residue
was triturated with ether (2.times.5 mL) and dried to give compound
8-3 (310 mg, 86%) as pale yellow solid.
[0437] To a solution of 8-3 (310 mg, 0.62 mmol) in THF (4 mL) and
H.sub.2O (1 mL) was added LiOH.H.sub.2O (77 mg, 1.86 mmol) and DIEA
(279 mg, 2.17 mmol). The solution was stirred at rt overnight.
After removal of solvent, the residue was purified by prep-HPLC
(water and ACN, 0.1% formic acid) to give compound 8-4 (140 mg,
56%).
[0438] To a solution of 8-4 (140 mg, 0.34 mmol) in DCM (4 mL) was
added TEA (172 mg, 1.72 mmol) and MsCl (79 mg, 0.85 mmol). The
solution was stirred at rt for 4 h. DCM (10 mL) was added. The
organics were washed with water (2.times.10 mL), brine (10 mL),
dried over Na.sub.2SO.sub.4, and concentrated. The residue was
dried under high vacuum to give crude 8-5 (171 mg).
[0439] To a solution of 8-5 (170 mg, 0.3 mmol) in DMF (2 mL) was
added LiCl (252 mg, 6.0 mmol). The mixture was stirred for 2 h at
rt and then 60.degree. C. overnight. After removal of solvent, DCM
(10 mL) was added. The organic layer was washed with water (10 mL),
brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated to
give a residue. The residue was purified by prep-HPLC (water and
ACN, 0.1% formic acid) to give compound 8-6 (86 mg, 64% in two
steps) as off-white powder. LCMS: 443 [M+H].sup.+. .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 7.25 (d, J=7.8 Hz, 2H), 6.72 (d, J=7.8 Hz,
2H), 6.00 (m, 1H), 5.71 (m, 1H), 5.18 (s, 1H), 3.71-3.61 (m, 8H),
2.27-1.67 (m, 8H), 1.28 (s, 1H), 1.12 (s, 3H).
[0440] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
[0441] The disclosures illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," "containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the disclosure claimed.
[0442] Thus, it should be understood that although the present
disclosure has been specifically disclosed by preferred embodiments
and optional features, modification, improvement and variation of
the disclosures embodied therein herein disclosed may be resorted
to by those skilled in the art, and that such modifications,
improvements and variations are considered to be within the scope
of this disclosure. The materials, methods, and examples provided
here are representative of preferred embodiments, are exemplary,
and are not intended as limitations on the scope of the
disclosure.
[0443] The disclosure has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
disclosure. This includes the generic description of the disclosure
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[0444] In addition, where features or aspects of the disclosure are
described in terms of Markush groups, those skilled in the art will
recognize that the disclosure is also thereby described in terms of
any individual member or subgroup of members of the Markush
group.
[0445] All publications, patent applications, patents, and other
references mentioned herein are expressly incorporated by reference
in their entirety, to the same extent as if each were incorporated
by reference individually. In case of conflict, the present
specification, including definitions, will control.
[0446] It is to be understood that while the disclosure has been
described in conjunction with the above embodiments, that the
foregoing description and examples are intended to illustrate and
not limit the scope of the disclosure. Other aspects, advantages
and modifications within the scope of the disclosure will be
apparent to those skilled in the art to which the disclosure
pertains.
* * * * *